KR19990015206A - Substituted aromatic derivatives with selective thrombin inhibitory activity - Google Patents

Abstract

The present invention relates to an aromatic compound substituted by an amidino group represented by the following formula (1) exhibiting a potent but selective thrombin inhibitory activity, a novel preparation method of the compound represented by the formula (1), and a pharmaceutically acceptable carrier, The present invention relates to a thrombin inhibitor composition which is characterized by containing a compound as an active ingredient and exhibits an excellent efficacy for the prevention and treatment of thrombosis.

[Chemical Formula 1]

In this formula,

A is or , Wherein m represents an integer of 0 to 2,

R ₁ and R ₂ each independently represent hydrogen or together with the carbon atom to which they are attached form a fused benzene ring,

n represents an integer of 0 to 2,

X represents CH ₂ , CO or SO ₂ ,

Y represents any one of the following formulas (2) to (8)

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

-CH ₂ -NR ₁₁ R ₁₂

(7)

[Chemical Formula 8]

T represents - (CH ₂ ) _q -, - (CH ₂ ) _q -SO ₂ - or alkenyl, wherein q represents an integer of 0 to 2,

R ₃ represents hydrogen, alkyl, alkoxy, nitro, benzoyl or -NR ₄ R ₅ wherein R ₄ and R ₅ each independently represent hydrogen or alkylsulfonyl,

R < ₆ > represents hydrogen or alkyl,

D is , Cycloalkyl or naphthyl,

R < ₇ > represents hydrogen or alkylsulfonyl,

R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ each independently represent hydrogen, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl or carbamoylalkyl,

E represents cycloalkyl,

R ₁₁ and R ₁₂ each independently represent naphthylalkyl.

Description

Substituted aromatic derivatives with selective thrombin inhibitory activity (assdf)

The present invention relates to novel aromatic compounds substituted by amidino groups. More particularly, the present invention relates to aromatic compounds and salts thereof substituted by an amidino group of the formula (1) which exhibits a potent but selective thrombin inhibitory activity:

[Chemical Formula 1]

In this formula,

A is or , Wherein m represents an integer of 0 to 2,

R ₁ and R ₂ each independently represent hydrogen or together with the carbon atom to which they are attached form a fused benzene ring,

n represents an integer of 0 to 2,

X represents CH ₂ , CO or SO ₂ ,

Y represents any one of the following formulas (2) to (8)

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

-CH ₂ -NR ₁₁ R ₁₂

(7)

[Chemical Formula 8]

T represents - (CH ₂ ) _q -, - (CH ₂ ) _q -SO ₂ - or alkenyl, wherein q represents an integer of 0 to 2,

R ₃ represents hydrogen, alkyl, alkoxy, nitro, benzoyl or -NR ₄ R ₅ wherein R ₄ and R ₅ each independently represent hydrogen or alkylsulfonyl,

R < ₆ > represents hydrogen or alkyl,

D is , Cycloalkyl or naphthyl,

R < ₇ > represents hydrogen or alkylsulfonyl,

R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ each independently represent hydrogen, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl or carbamoylalkyl,

E represents cycloalkyl,

R ₁₁ and R ₁₂ each independently represent naphthylalkyl.

The present invention also relates to a novel process for the preparation of the compound of formula 1, the novel intermediates used as starting materials in the preparation of the compound of formula 1, and the pharmaceutically acceptable carrier, The present invention relates to a thrombin inhibitor composition having an excellent effect for the prevention and treatment of thrombosis.

It is known that various kinds of proteolytic enzymes are present in vivo. Among them, thrombin, factor Xa, factor IXa, factor VIIa, trypsin, plasmin, tissue plasminogen activator, carcranin, A group of serine proteases such as C3 / C5 converting enzyme and tryptase are known. If such a protease is abnormally activated for any reason, various diseases may be caused. Therefore, it is expected that substances having inhibitory activity against these proteases can be used once as clinically useful therapeutic agents. For example, an antithrombin agent, an anti-factor Xa agent and a factor VIIa agent are useful as therapeutic agents for thrombosis, antitrypsin agents are useful for the treatment of pancreatitis, antiplasmin agents are useful as hemostatic agents, antiallergic agents, Anticancer agents are useful as therapeutic agents for inflammation and ulcers, and the serotonergic system is useful as a therapeutic agent for nephritis and rheumatism.

Of these inhibitors for proteolytic enzymes, thrombin inhibitors have recently become a subject of interest as therapeutic agents for thrombosis, which is one of the most common adult diseases. The thrombin inhibitor is an agent that acts to prevent the coagulation of blood by blocking the activity of thrombin involved in the coagulation process of blood. In general, it is known that various complex enzyme reactions are involved in the blood coagulation process. The final step involves the conversion of prothrombin to thrombin. The thrombin generated in this reaction plays a role of activating the platelets and changing the fibrinogen to fibrin. Since the fibrin is converted into a polymer substance by the polymerization reaction and is cross-linked by the activated blood factor XIII, It plays a very important role in blood coagulation. Therefore, the thrombin inhibitor can act as an effective anticoagulant and inhibit platelet activity and inhibit fibrinogenesis and stabilization. Therefore, it has long been known that thrombin inhibition can be inhibited by using these compounds to prevent blood coagulation and to treat various types of thrombosis Methods have been tried.

However, since thrombin is one of various serine proteases present in the blood of the human body, compounds capable of inhibiting thrombin may be used in a similar manner to other serine proteases other than thrombin such as trypsin and plasmin It has a property that can be suppressed. Therefore, in developing the thrombin inhibitor, it is very important to have a property of selectively suppressing thrombin more effectively than trypsin, which is a prototype of the serine protease in consideration of the characteristics of thrombin.

European Patent Publication No. 623595 discloses guanidinyl or amidinyl substituted heterocyclic thrombin inhibitors as thrombin inhibitors having a structure similar to the compound of formula (1) according to the present invention. However, the compound has insufficient selective inhibitory effect on thrombin as compared with general serine protease, so that it is not preferable to use for the purpose of preventing blood coagulation and treating thrombosis.

Therefore, the present inventors conducted extensive and continuous studies to develop selective thrombin inhibitors that inhibit thrombin effectively and have a relatively low inhibitory activity against trypsin. As a result, the compound of the formula (1) And the present invention has been completed.

Accordingly, the present invention relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof, which exhibit selective thrombin inhibitory activity.

The present invention also relates to a method of preparing a compound of formula (I) and a salt thereof, and to a thrombin inhibitor composition comprising a compound of formula (I) as an active ingredient together with a pharmaceutically acceptable carrier.

Among the compounds of formula (1) having selective thrombin inhibitory activity, preferred compounds are

A is or , Wherein m represents 0 or 1,

R ₁ and R ₂ each independently represent hydrogen or together with the carbon atom to which they are attached form a fused benzene ring,

n represents 0 or 1,

X represents CH ₂ , CO or SO ₂ ,

Y represents any one of the groups represented by formulas (2) to (8)

T represents - (CH ₂ ) _q -, - (CH ₂ ) _q -SO ₂ - or ethenyl, wherein q is an integer from 0 to 2,

R ₃ represents hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, benzoyl or -NR ₄ R ₅ wherein R ₄ and R ₅ are each independently hydrogen or C ₁ -C ₄ alkyl Sulfonyl,

R ₆ represents hydrogen or C ₁ -C ₄ alkyl,

D is , C ₄ -C ₇ cycloalkyl or naphthyl,

R ₇ represents hydrogen or C ₁ -C ₄ alkylsulfonyl,

R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, hydroxycarbonyl lower alkyl, lower alkoxycarbonyl lower alkyl, C ₁ -C ₄ alkylsulfonyl or carbamoyl lower Alkyl,

E represents C ₄ -C ₇ cycloalkyl,

R ₁₁ and R ₁₂ each independently represent a naphthylmethyl group.

More preferred compounds among the preferred compounds of formula (1)

A is or , Wherein m represents 0 or 1,

R ₁ and R ₂ each independently represent hydrogen or together with the carbon atom to which they are attached form a fused benzene ring,

n represents 0 or 1,

X represents CH ₂ , CO or SO ₂ ,

Y represents any one of the groups represented by formulas (2) to (8)

T is - (CH _{2) q} -, - (CH _{2) q} -SO ₂ - or a represents an ethenyl, where q is - (CH _{2) q} - from 0 to 2 integer in the case of a - (CH ₂ ) _q -SO ₂ - represents 1 in the case of,

R ₃ represents hydrogen, methyl, methoxy, nitro, benzoyl or -NR ₄ R ₅ wherein R ₄ and R ₅ each independently represent hydrogen or methylsulfonyl,

R < ₆ > represents hydrogen or methyl,

D is , Cyclohexyl or naphthyl,

R < ₇ > represents hydrogen or methylsulfonyl,

R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ are each independently hydrogen, hydroxycarbonylmethyl, ethoxycarbonylmethyl, methylsulfonyl or carbamoylmethyl,

E represents cyclohexyl,

R ₁₁ and R ₁₂ each independently represent a naphthylmethyl group.

Representative examples of the compound of the formula (1) according to the present invention include the following compounds.

4 - (((1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine,

4 - (((1 - ((4-methylphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine,

4 - (((1- (naphthylsulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine,

Propyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine, 2-methyl-2-

4 - (((1- (S) - (3-phenylpropanoyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarboxamidine,

4 - (((- (2- (3-methylphenyl) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine, or

3 - (((1- (2 - ((4-methoxyphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine.

The compounds of formula (I) according to the present invention can also form pharmaceutically acceptable salts, and these salts are also included in the present invention. Such pharmaceutically acceptable salts include those acids which form pharmaceutically acceptable anions and which form non-toxic acid addition salts such as hydrochloric acid, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carboxylic acids such as acetic acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and the like, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid And the like.

Such an acid addition salt can be easily prepared by applying a conversion process customary to those skilled in the art to the compound of formula (I) in salt-free form.

In the compound of formula (I) according to the present invention, when Y is a group of the formula (3), (4), (5) or (8), these compounds may contain an asymmetric carbon atom in the molecule thereof. 1: 1 < / RTI > mixture. In some cases, the compound of formula (I) may contain a double bond in the molecule and may exist as a geometric isomer in this case. Thus, the scope of the present invention includes such optical isomers and geometric isomers.

The present invention also relates to a process for preparing a compound of formula (1).

According to the method of the present invention, in order to produce the desired compound of formula (1) and a salt thereof,

(a) reacting a compound of the following formula (9) with a compound of the following formula (10) to obtain a compound of the formula (17a)

(b) reacting a compound of the formula (11) or a salt thereof with a compound of the following formula (12) to obtain a compound of the formula (17)

(c) reacting a compound of the following formula (13) with a compound of the following formula (14) to obtain a compound of the formula (17b)

(d) reacting a compound of the following formula (15) or a salt thereof with a compound of the following formula (16) to obtain a compound of the formula (17c) wherein Y is a group of the formula (3)

(e) converting the cyano group of the compound prepared by any one of the above methods (a) to (d) into an amidino group.

[Chemical Formula 9]

[Chemical formula 10]

[Formula 17a]

(11)

[Chemical Formula 12]

L-X-Y

[Chemical Formula 17]

[Chemical Formula 13]

[Chemical Formula 14]

[Formula 17b]

[Chemical Formula 15]

[Chemical Formula 16]

L-X-D

[Chemical Formula 17c]

In the above formula

A, R ₁ , R ₂ , R ₆ , n, m, X, Y and D are as defined above,

L represents a leaving group, preferably halogen or hydroxy.

Among the numbers of the above formulas, 17b is a case where A is , And 17c represents Y .

The methods (a) to (e) for preparing the compound of formula (1) according to the present invention will be described in more detail with the reaction formula.

[Reaction Scheme 1]

In method (a) shown in Scheme 1, a bromo compound of formula (9) is reacted with a hydroxy compound of formula (10) to liberate hydrobromic acid to produce a compound of formula (17a). The reaction of the compound of formula (9) with the compound of formula (10) can be preferably carried out in a reaction-inert organic solvent. Examples of the solvent that can be preferably used for this purpose include polar solvents such as ethers such as tetrahydrofuran, diethyl ether and dioxane, N, N-dimethylformamide and dimethyl sulfoxide, and hexamethylphosphoramide Nitriles such as acetonitrile and propionitrile, halogenated hydrocarbons such as methylene chloride, dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, pyridine, and mixtures thereof , A mixture of dimethyl sulfoxide and tetrahydrofuran is particularly preferably used.

The reaction (a) can be carried out in the presence of a base, if necessary, where the base can act as a catalyst and act as an acid acceptor of the hydrobromic acid resulting from the reaction. Examples of bases which can be preferably used for such purposes include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, ammonium salts of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, magnesium carbonate and sodium bicarbonate, sodium hydrogen hydride, potassium hydride Or an alkali metal hydride such as an alkali metal hydride such as triethylamine, pyridine, diisopropylethylamine, N, N-dimethylaniline, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [ 5,4,0] undec-7-ene (DBU), and 1,4-diazabicyclo [2,2,2] octane (DABCO). A particularly preferred base for use in this reaction is sodium hydride.

The reaction temperature and time in this reaction are not critical and are generally carried out under cooling, heating or heating for 2 to 12 hours. The reaction is preferably carried out at a temperature of 0 to 40 DEG C for 2 to 5 hours.

[Reaction Scheme 2]

In the method (b) shown in Scheme 2, the amine compound of the formula (11) or its salt is coupled with the compound of the formula (12) to prepare the compound of the formula (17). The coupling reaction of the compound of the formula (11) and the compound of the formula (12) can be carried out preferably in a reaction-inert organic solvent, and also in the presence of a base, good results can be obtained. The solvent and the base usable for this purpose may be the same as those described for the method (a), but in the process (b), alcohols may also be used as the solvent. The same conditions as described for the method (a) can be applied to the reaction time and the temperature.

The present reaction can also be carried out in the presence of a condensing agent if necessary. Examples of the condensing agent which can be preferably used include N, N-diethylcarbodiimide, 1-ethyl-3- (3- dimethylaminopropyl) (WSCI), N, N-dicyclohexylcarbodiimide, and the like. Examples of the carbodiimide compound include triphenylphosphine (PPh ₃ ) and diethyl azodicarboxylate (DEAD) .

[Reaction Scheme 3]

In the method (c) shown in Scheme 3, the phosphonium chloride compound of Formula 13 is reacted with the aldehyde compound of Formula 14 to prepare an ethenyl compound of Formula 17b. The reaction is preferably carried out in the presence of a reaction-inert organic solvent and a base. Examples of the solvent and base usable herein include the same ones as described for the method (a), and a mixed solvent with ethanol It is also possible. Among these solvents, particularly preferred solvents include 1: 1 (v / v) mixtures of tetrahydrofuran and ethanol. Examples of the solvent include 1,8-diazabicyclo [5,4,0] undeca- 7-yen.

The same conditions as described for the method (a) can be applied to the reaction time and the temperature.

[Reaction Scheme 4]

In method (d) shown in Scheme 4, the compound of formula (15) or its salt is subjected to coupling reaction with the compound of formula (16) to produce the compound of formula (17c) wherein Y represents the group of formula (3). The reaction can be carried out under the same reaction conditions as described for the process (b), particularly preferably using methylene chloride or methanol as the solvent and using triethylamine as the base.

The compounds prepared by the above-described methods (a) to (d) are all aromatic compounds of formula (17) substituted by cyano groups. The compound of formula (17) is a novel compound itself as an intermediate to be passed through in the process of preparing the compound of formula (1) according to the present invention. Accordingly, it is an object of the present invention to provide the novel intermediate compound of formula (17).

On the other hand, in order to obtain the compound of the formula (1) substituted by the amidino group, the conversion of the cyano group into the amidino group should be carried out according to the process (e) shown in the following reaction formula (5).

[Reaction Scheme 5]

In the method (e) of converting the cyano group in the compound of formula (17) into the amidino group to prepare the compound of formula (1), firstly a saturated HCl-EtOH solution in an organic solvent such as methylene chloride or after processing using only the saturated HCl-EtOH solution, and the reaction proceeds by treatment with a saturated solution of NH ₃ -EtOH. However, these reaction conditions are only one example, and the compound of the formula (1) can be prepared as much as usual using other methods of converting the cyano group into the amidino group.

The reaction temperature and time in the above reaction are not critical, and can be preferably carried out at room temperature, heating or heating.

The compound of formula (1) according to the present invention, prepared according to the above-described method, can further be used for deprotecting an amino protecting group such as t-butoxycarbonyl, introducing a substituent into an amine group, reducing the nitro group to an amino group For example, by using various reactions such as a reaction using palladium-carbon and pressurized hydrogen conditions, and each reaction carried out for this purpose can be carried out in a conventional manner in the art Method can be applied.

The resulting compound of formula (1) and its salt are purified and purified by conventional post treatment methods, for example, column chromatography or recrystallization.

The compounds of formulas (9), (12), (13) and (16) used as starting materials in the method according to the present invention are all commercially available compounds, to be. Accordingly, it is another object of the present invention to provide novel compounds of formulas (10), (11), (14) and (15) used for preparing the compound of formula (1).

The novel intermediate compounds of formulas (10), (11), (14) and (15) can be prepared according to the methods described specifically in conjunction with the reaction conditions below in Schemes 6 to 9.

[Reaction Scheme 6]

[Reaction Scheme 7]

[Reaction Scheme 8]

[Reaction Scheme 9]

The above-mentioned synthesis methods will be more specifically described in the following embodiments.

The present invention also relates to a thrombin inhibitor composition characterized by comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier. The composition according to the present invention not only exhibits a strong thrombin inhibitory activity but also exhibits remarkably excellent activity, that is, selective thrombin inhibitory activity, in comparison with trypsin, and thus can be usefully used as a thrombotic prophylactic and therapeutic agent.

When a compound of the present invention is administered for clinical purposes, an effective daily dose is generally in the range of 0.1 to 30 mg, preferably 0.5 to 10 mg per kg of body weight. However, the dosage appropriate for the individual patient may be determined by a specialist in consideration of the specific compound to be administered, the weight, sex, health condition, diet, administration time, administration method, excrement, Lt; / RTI >

The composition containing the compound of formula (1) according to the present invention may be prepared in the form of injectable preparations, for example in the form of sterile injectable aqueous or oleagenous suspensions, using suitable dispersing, wetting or suspending agents according to techniques known in the art have. Waterborne solvents that may be used herein include water, Ringer's solution, or an isocratic NaCl solution, and sterile, fixed oils are typically used as a solvent or suspending medium. Any non-irritating fixed oils, including mono-, di-glycerides, may be used for this purpose, and fatty acids such as oleic acid may also be used in the injectable formulation.

A preferred pharmaceutical formulation is in unit dosage form. In such form, the agent is subdivided into unit forms comprising an appropriate amount of active ingredient. The unit dosage form can be a packaged preparation and the package contains a discrete amount of the formulation.

In addition, according to the experimental results, it was confirmed that the compound of Chemical Formula 1 according to the present invention exhibits a strong thrombin inhibitory effect without showing acute toxicity to mammals such as rats and dogs.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, these examples and experimental examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

[Production Example 1]

(3-1,2,3,4-tetrahydroisoquinolyl) methan-1-ol Synthesis of

0.95 g (25 mmol) of lithium aluminum hydride was suspended in 40 ml of anhydrous tetrahydrofuran and stirred at room temperature for 30 minutes. To the resultant suspension was added a solution of 4.27 g (20 mmol) of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride and 5.5 ml (40 mmol) of triethylamine in 40 ml of anhydrous tetrahydrofuran Was added dropwise. The reaction mixture was refluxed for 3 hours, then cooled to room temperature, poured into 100 g of finely crushed ice and acidified with 30 mL of 1N HCl. After stirring for 30 min, insoluble solids were removed by filtration. It was neutralized with 30 ml of 1N NaOH and extracted with dichloromethane and water. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (Kiselgel 60, eluent chloroform: methanol = 9: 1 - > 3: 1) to give 0.54 g (3.31 mmol, Yield: 17%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 2.58-2.77 (m, 2H), 3.13 (bs, 3H), 3.57 (dt, 1H, J = 7.7Hz, 11.1Hz), 3.82 (dd, 1H, J = 3.7 Hz, 11.1 Hz), 4.05 (s, 2H), 6.98-7.04 (m, 1H), 7.06-7.17

[Example 1]

Synthesis of 1 - ((4-methoxyphenyl) sulfonyl) piperidine-3-carbaldehyde

720 mg of 1- (4-methoxyphenylsulfonyl) -3- (hydroxymethyl) piperidine was dissolved in 20 ml of methylene chloride, 5.7 g of PDC was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, eluent ethyl acetate: n-hexane = 1: 2) to give 242 mg (yield 34%) of the title compound as a white solid. ≪ / RTI >

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 9.68 (s, 1H), 7.72 (d, 2H, J = 15.0Hz), 7.02 (d 2H, J = 15.0Hz.), 3.88 (s, 3H), 2H), 1.41-1.95 (m, 4H), 2.35-2.80 (m,

[Example 2]

Synthesis of 4- (2- (1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyl) vinyl) benzenecarbonitrile

223 mg (0.00079 mol) of 1- (4-methoxyphenylsulfonyl) -3- (formyl) piperidine and 358 mg (0.00087 mol) of (4-cyanobenzyl) triphenylphosphonium chloride were dissolved in tetrahydrofuran 7 ml of ethanol, 0.13 ml (0.00087 mol) of DBU was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent ethyl acetate: n-hexane = 1: 3) to obtain 265 mg (yield 88%) of the title compound as a white foamy solid .

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 6.98-7.72 (m, 8H), 5.54-6.48 (m, 2H), 3.88 (d, 3H), 3.61-3.65 (m, 2H), 1.15-2.88 ( m, 7H)

[Example 3]

Synthesis of 4 - (((1- (naphthylmethyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

200 mg (0.00075 mol) of 3- (4-cyanobenzyloxymethyl) piperidine hydrochloride, 119 mg (0.00075 mol) of -hydroxymethylnaphthalene and 216 mg (0.00083 mol) of triphenylphosphine were dissolved in dichloromethane After dissolution, 0.13 ml (0.00083 mol) of DEAD was slowly added to the solution under ice-cooling. After the reaction was allowed to proceed overnight at room temperature, the reaction mixture was evaporated under reduced pressure, and 10 ml of a 1: 1 mixed solution of ethyl acetate and n-hexane was added thereto and stirred for 1 hour. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (silica gel, eluent ethyl acetate: n-hexane = 1: 3) to give 45 mg (yield 16%) of the title compound as a colorless liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.29-8.33 (m, 11H), 4.42 (d, 2H, J = 3.3Hz), 4.13 (d, 2H, J = 7.0Hz), 3.36 (d, 2H , J = 6.0 Hz), 2.73-2.88 (m, 2H), 1.23-2.16 (m, 7H)

[Example 4]

Synthesis of 4 - (((R) -pyrrolidin-2-ylmethoxy) methyl) benzenecarbonitrile hydrochloride

(0.0569 mol) of (S) -1- (t-butylcyclohexyl) -2- (4-cyanobenzyloxymethyl) pyrrolidine was dissolved in 25 ml of dichloromethane, 80 ml of HCl was added and the mixture was stirred for 2 hours and further stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dried under vacuum to give 14.4 g (0.0569 mol) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.84-2.14 (4H, m), 3.30 (2H, brs), 3.72-3.77 (1H, m), 3.83-3.87 (2H, m), 4.61-4.74 ( M), 7.52-7.55 (2H, m), 7.62-7.64 (2H, m), 9.54 (1H, br s), 10.17

[Example 5]

Synthesis of 4 - (((1- (R) - (+) - 2-amino-3-cyclohexylpropanoyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

(Yield: 100%) was obtained as a white foamy solid by the same procedure as in Example 4. 1H-NMR (DMSO-d6)?

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 8.51 (bs, 2H), 7.45-7.64 (m, 4H), 4.59-4.71 (m, 1H), 4.55 (s, 2H), 3.84-4.40 (m, 2H), 3.42 (bs, 2H), 2.63-3.28 (m, 2H), 0.75-1.90 (m, 18H)

[Example 6]

Synthesis of 4 - (((3-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

The reaction was carried out in the same manner as in Example 4 using 9 g (0.027 mol) of 1- (t-butoxycarbonyl) -3- (±) - (4-cyanobenzyloxymethyl) piperidine to obtain a pale yellow solid 5.295 g (yield 73%) of the title compound was obtained.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.63 (d, 2H, J = 8.3Hz), 7.43 (d, 2H, J = 8.1Hz), 4.53 (s, 2H), 3.32-3.34 (dd, 2H ), 3.00-3.15 (m, 2H), 2.35-2.60 (m, 2H), 1.15-1.85 (m, 5H)

[Example 7]

Synthesis of 3 - (((1- (2-aminoacetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

The reaction was carried out in the same manner as in Example 4 to give 4.77 g (14.7 mmol, Yield 98%) of the title compound.

¹ H-NMR (DMSO-d ₆ , ppm) ?: 1.22-1.53 (m, 2H), 1.59-1.97 (m, 3H), 2.65 (t, 0.5H, J = 11.0Hz), 2.83-3.09 (M, 2.5H), 4.09 (d, 0.5H, J = 12.0 Hz), 4.29 (d, 0.5 Hz, J = 9.7 Hz), 4.55 (d, 2H, J = 7.1 Hz), 7.59-7.67 (m, IH), 7.69-7.73 (m, IH), 7.77-7.81

[Example 8]

Synthesis of 3 - (((3-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

The reaction was carried out in the same manner as in Example 4 to give 7.56 g (0.028 mol, yield 95%) of the title compound.

^{1 H-NMR (DMSO-d} 6, ppm) δ: 1.17-1.34 (m, 1H), 1.58-1.82 (m, 3H), 2.09 (bs, 1H), 2.64 (t, 1H, J = 12.0Hz) 1H), 2.76 (t, 1H, J = 12.0 Hz), 3.18-3.47 (m, 4H), 4.53 (s, 2H), 7.59 Hz), 7.78 (bs, 2H), 8.8 (bs, 2H)

[Example 9]

Synthesis of 3 - (((2-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

5.43 g (0.020 mol, yield 93%) of the title compound were obtained using the same method as in Example 4.

^{1 H-NMR (DMSO-d} 6, ppm) δ: 1.40-1.60 (m, 2H), 1.61-1.85 (m, 4H), 2.82-2.97 (m, 1H), 3.20-3.42 (m, 2H), 1H), 7.89 (s, 1H), 8.89 (bs, 1H), 7.59-7.40 (m, 2H)

[Example 10]

Synthesis of 4 - (((1- (2-aminoacetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 4 to give the title compound (0.81 g, 2.5 mmol, Yield: quant.).

^{1 H-NMR (DMSO-d} 6, ppm) δ: 1.21-1.52 (m, 2H), 1.57-1.94 (m, 3H), 2.66 (t, 0.5H, J = 12.0Hz), 2.84-3.08 (m 2H), 3.84 (bs, 2H), 4.04 (d, 0.5H, J = 12.0 Hz), 4.29 (d, 0.5H, J = 8.15 (bs, 3H), 7.54 (t, 2H, J = 7.6 Hz), 7.85 (d, 2H, J = 8.2 Hz)

[Example 11]

Synthesis of 4 - (((1-2- (S) -aminopropanoyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

The reaction was carried out in the same manner as in Example 4 to give 3.30 g (9.8 mmol, Yield 98%) of the title compound.

^{1 H-NMR (DMSO-d} 6, ppm) δ: 1.21-1.42 (m, 4H), 1.43-1.83 (m, 5H), 2.69 (t, 0.5H, J = 12.0Hz), 3.14 (t, 0.5 (M, 2H), 4.87 (bs, 0.5H), 4.19-4.48 (m, H), 7.49-7.57 (m, 2H), 7.80-7.89 (m, 2H), 8.16 (bs,

[Example 12]

Synthesis of 4 - (((1- (2-aminoacetyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 4 to give 3.22 g (9.94 mmol, Yield: quant.) Of the title compound.

^{1 H-NMR (DMSO-d} 6, ppm) δ: 1.17-1.84 (m, 6H), 2.68 (t, 0.5H, J = 13.0Hz), 3.06 (t, 0.5H, J = 13.0Hz), 3.47 2H), 4.77 (bs, 1H), 4.32 (d, 0.5H, J = 13.1 Hz), 4.58-4.66 (m, 2H) 2H), 7.51 (t, 2H, J = 6.4 Hz), 7.84 (d, 2H, J = 8.2 Hz), 8.11

[Example 13]

Synthesis of 4 - (((2-piperidyl) methoxy) methyl) benzenecarbonitrile hydrochloride

The reaction was carried out in the same manner as in Example 4 to obtain 5.39 g (0.030 mol, yield 92%) of the title compound.

^{1 H-NMR (DMSO-d} 6, ppm) δ: 1.38-1.67 (m, 3H), 1.76 (bs, 3H), 2.88 (bs, 1H), 3.17-3.39 (m, 2H), 3.56-3.67 ( 2H, J = 8.3Hz), 8.64-8.90 (m, 2H), 7.66 (d, 2H, J =

[Example 14]

Pyrrolidin-2-yl) methoxy) methyl) benzenecarbonitrile The title compound was synthesized in the same manner as in (1) except that

600 mg (1.451 mmol) of 1- [1- (t-butoxycarbonyl) -2 (R) -pyrrolidinoyl] -2 (S) After dissolving in 5 ml of methane, 5 ml of trifluoroacetic acid was added dropwise under ice-cooling, and the mixture was stirred for 1 hour and 30 minutes. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent dichloromethane: methanol = 10: 1) to give 470 mg (yield 99%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.85-2.20 (8H, m), 2.81-2.85 (2H, m), 3.24-3.50 (4H, m), 3.71-3.75 (1H, m), 4.14- (1H, m), 4.19 (1H, m), 4.51-4.53 (2H, m), 7.36-7.40 (2H, m), 7.65-7.68

[Example 15]

Synthesis of t-butyl 2- (R) - ((2- (S) - ((4-cyanophenyl) methoxy) methyl) pyrrolidinyl) carbonyl) pyrrolidinecarboxylate

(1.978 mmol) of (S) -2- (4-cyanobenzyloxymethyl) pyrrolidine hydrochloride was dissolved in 20 ml of dichloromethane, followed by addition of 485 mg (3.956 mmol) 640 mg (2.968 mmol) of N- (t-butoxycarbonyl) proline and 760 mg (3.956 mmol) of WSCI-HCl were added and stirred for 30 minutes and then further at room temperature for 12 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent ethyl acetate: n-hexane = 4: 1) to give 680 mg (yield 83%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.37 (4H, s), 1.46 (5H, s), 1.89-2.14 (8H, m), 3.42-3.44 (2H, m), 3.53-3.64 m), 4.21-4.38 (2H, m), 4.62 (2H, s), 7.43-7.49 (2H, m), 7.62-7.71

[Example 16]

butyl 3 (R) - ((2 (S) - ((4-cyanophenyl) methoxy) methyl) pyrrolidinyl) carbonyl) -1,3,4-trihydroisoquinolin- (S) - ((2 (S) - ((4-cyanophenyl) methoxy) methyl) pyrrolidinyl) carbonyl) -1,3,4-trihydroisoquinoline -2-carboxylate < / RTI &

The reaction was carried out in the same manner as in Example 15 to separate and separate the two diastereomers of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.04-7.67 (m, 8H), 4.27-5.05 (m, 6H), 3.55-3.65 (m, 4H), 3.02-3.09 (m, 2H), 1.99- 2.05 (m, 4H), 1.43 (d, 9H, J = 18.0 Hz)

¹ H NMR (CDCl ₃ , ppm)?: 7.00-7.64 (m, 8H), 4.27-5.06 (m, 6H), 3.46-3.58 (m, 4H), 1.48 (d, 9H, J = 10.0 Hz)

[Example 17]

Synthesis of 4 - (((1- (S) - (2-phenylacetyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarbonyltryl

The reaction was carried out in the same manner as in Example 15 to give 206 mg (yield 78%) of the title compound as a colorless liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.22-7.86 (m, 9H), 4.53 (s, 2H), 4.32 (bs, 1H), 3.59-3.71 (m, 4H), 3.39-3.49 (m, 2H), 1.86-2.05 (m, 4H)

[Example 18]

Methyl) piperidyl) -1- (cyclohexylmethyl) -2-oxoethyl) (t-butoxy) - < / RTI & Synthesis of formamide

The reaction was carried out in the same manner as in Example 15 to give 412 mg (yield 36%) of the title compound as a white foamy solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.42-7.66 (m, 4H), 5.25-5.30 (m, 1H), 4.70-4.72 (m, 1H), 4.50 (s, 2H), 4.33-4.60 ( 2H), 0.76-1.94 (m, 18H), 3.72-3.02 (m, 2H)

[Example 19]

Synthesis of 4 - (((1- (2- (phenylsulfonyl) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to give 75 mg (yield 22%) of the title compound as a colorless liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.90-7.94 (m, 2H), 7.41-7.90 (m, 7H), 4.53 (s, 1H), 4.26 (s, 1H), 4.17-4.61 (m, 2H), 3.39-3.46 (m, 2H), 3.08-3.16 (m, 1H), 2.74-2.91

[Example 20]

Synthesis of 4 - (((1- (R) - ((1- (methylsulfonyl) pyrrolidin-2-yl) carbonyl-3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to give 152 mg (yield 54%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.62-7.67 (m, 2H), 7.42-7.45 (m, 2H), 4.85-4.89 (m, 1H), 4.54 (s, 2H), 3.45-3.71 ( (m, 2H), 3.36-3.41 (m, 2H), 3.06 (s, 1.5H), 3.01 (s, 1.5H), 3.16-3.29 2.26 (m, 11 H)

[Example 21]

Synthesis of 4 - (((1- (2-phenylacetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to give 243 mg (yield 62%) of the title compound as a colorless liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.61-7.66 (m, 2H), 7.22-7.44 (m, 7H), 4.53 (s, 1Ha), 4.45 (s, 1Hb), 4.37-4.49 (m, 2H), 3.74 (s, 2H), 3.71-3.91 (m, 1H), 3.22-3.37 (m, 2H), 2.61-3.05 m, 2H)

[Example 22]

(((1- (S) - (2 - ((phenylsulfonyl) amino) propanoyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to give 95 mg (yield 57%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.18-1.22 (3H, m), 1.23-1.31 (2H, m), 1.51-1.73 (3H, m), 2.22-2.48 (1H, m), 2.61- (1H, m), 2.86 (1H, m), 3.18-3.25 (2H, m), 3.41-3.58 (1H, m), 3.88-4.16 ), 7.32-7.48 (5H, m), 7.54-7.59 (2H, m), 7.75-7.77 (2H, m)

[Example 23]

Synthesis of 4 - (((1- (2- (2-nitrophenyl) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to give 225 mg (yield 76%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.26-1.51 (2H, m), 1.63-1.68 (1H, m), 1.82-1.95 (2H, m), 2.79-2.91 (0.5H, m), 3.01 (2H, m), 3.11-3.28 (1H, m), 3.41-3.49 (2H, m), 4.73-4.90 ), 4.55-4.61 (2H, m), 7.29-7.36 (1H, m), 7.44-7.49 (3H, m), 7.57-7.67 (3H, m), 8.10-8.14

[Example 24]

Synthesis of N- (2- (3 - ((3-cyanophenyl) methoxy) methyl) piperidyl) -2-oxoethyl) (t-butoxy)

The reaction was carried out in the same manner as in Example 15 to give the title compound (5.8 g, yield: quant.).

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.31-1.59 (m, 1H), 1.66-1.97 (m, 3H), 2.69 (t, 0.5H, J = 11.0Hz), 2.84-3.09 (m, 1.5 J = 13.0 Hz), 4.42 (d, 0.5H, J = 8 Hz), 3.28-3.42 (m, 2H), 3.55-3.73 2H), 5.54 (bs, 1H), 7.42-7.51 (m, 1H), 7.55-7.66 (m, 3H)

[Example 25]

Synthesis of N- (2- (3 - ((4-cyanophenyl) methoxy) methyl) piperidyl) -2-oxoethyl) (t-butoxy)

The reaction was carried out in the same manner as in Example 15 to give 0.967 g (2.50 mmol, Yield 83%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.22-1.55 (m, 11H), 1.58-1.93 (m, 3H), 2.66 (t, 0.5H, J = 11.0Hz), 2.82-3.07 (D, 0.5H, J = 12.0Hz), 3.96 (bs, 2H), 4.20 (d, 0.5H), 3.27-3.40 1H, J = 14.0 Hz), 4.41 (d, 0.5H, J = 12.0 Hz), 4.54 (s, 2H), 5.53 (bs, , 2H, J = 7.3 Hz)

[Example 26]

Synthesis of N- (2- (2 - ((4-cyanophenyl) methoxy) methyl) piperidyl) -1-methyl-2-oxoethyl) (t-butoxy)

The reaction was carried out in the same manner as in Example 15 to give 4.09 g (0.01 mole, yield: quant.) Of the title compound.

MS (ESI) m / e: 402 (M + H) +, 424 (M + Na) +

¹ H-NMR (CDCl ₃ , ppm)?: 1.17-1.34 (m, 3H), 1.38-1.52 (m, 11H), 1.54-1.87 ), 3.10 (t, 0.5H, J = 12.0 Hz), 3.49-3.79 (m, 2.5H), 4.09-4.20 (m, 0.5H), 4.42-4.67 2H, J = 8.1 Hz), 5.03 (bs, 0.5H), 5.56-5.70 (m,

[Example 27]

Synthesis of N- (2- (2 - ((4-cyanophenyl) methoxy) methyl) piperidyl) -2-oxoethyl) (t-butoxy)

The reaction was carried out in the same manner as in Example 15 to give 3.85 g (9.94 mmol, Yield: yield) of the title compound

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.45 (bs, 11H), 1.58-1.89 (m, 4H), 2.61 (t, 0.5H, J = 12.0Hz), 3.08 (t, 0.5H, J = (M, 2H), 3.46-3.82 (m, 2.5H), 3.90-4.19 (m, 2.5H), 4.48-4.67 (t, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.2 Hz)

[Example 28]

Synthesis of 4 - (((1- (2- (3-methylphenyl) acetyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to yield 0.36 g (1.0 mmol, Yield: quant.) Of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.19-1.84 (m, 6H), 2.30 (d, 3H, J = 6.4Hz), 2.55 (t, 0.5H, J = 11.3Hz), 2.98 (t, (M, 3H), 4.23 (bs, 0.5H), 4.47-4.70 (m, 2.5H), 5.08 (bs, 1H), 7.39 (d, 2H, J = 8.0 Hz), 7.59-7.66 (m, 2H)

[Example 29]

Synthesis of 4 - (((1 - ((3- (phenylcarbonyl) phenyl) carbonyl) -2-piperidyl) methoxy) methyl) ben zanecarbonitrile

The reaction was carried out in the same manner as in Example 15 to give 0.43 g (1 mmol, Yield: quant.) Of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.57 (bs, 2H), 1.71 (bs, 4H), 2.86 (bs, 0.5H) (t, 1H, J = 9.2 Hz), 4.14 (bs, 0.5H), 4.52 (bs, 3H), 5.16 (bs, 0.5H), 4.38 (bs, 2H), 7.42-7.66 7.71-7.85 (m, 4H)

[Example 30]

Synthesis of 4 - (((1- (3- (E) -phenylprop-2-enoyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 15 to yield 0.36 g (1.0 mmol, Yield: quant.) Of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.51 (bs, 2H), 1.62-1.93 (m, 4H), 2.71 (bs, 0.5H) , 3.77 (bs, 1H), 3.99 (bs, 0.5H), 4.42-4.73 (m, 3H), 5.12 (bs, 0.5H) / RTI > 7.69 (m, 5H)

[Example 31]

Synthesis of 3- (hydroxymethyl) -1 - ((4-methoxyphenyl) sulfonyl) piperidine

A solution of 1.2 g (0.010 mol) of 3-piperidinemethanol and 1.6 ml (0.012 mol) of triethylamine in 40 ml of dichloromethane was cooled in an ice-water bath. 2.1 g (0.010 mol) of 4-methoxybenzenesulfonyl chloride were added and the solution was stirred at ambient temperature for 3.5 hours. The reaction mixture was extracted with dichloromethane and water, and the organic layer was dried over sodium sulfate. The filtrate was concentrated under reduced pressure and dried under vacuum to give 2.81 g (98% yield) of the title compound as an amorphous solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.06 (m, 1H), 1.47-1.81 (m, 4H), 1.89 (bs, 1H), 2.27 (t, 1H, J = 10.0Hz), 2.37-2.48 (m, 1H), 3.46-3.67 (m, 4H), 3.88 (s, 3H), 7.01 (d, 2H, J = 9.8Hz)

[Example 32]

Synthesis of 2- (hydroxymethyl) -1 - ((4-methoxyphenyl) sulfonyl) piperidine

The reaction was carried out in the same manner as in Example 31 to give 2.15 g (7.53 mmol, Yield: 75%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.20-1.56 (m, 5H), 1.99 (bs, 1H), 3.11 (t, 1H, J = 14.2 Hz), 3.50-3.61 2H, J = 8.9 Hz), 3.81 (d, 2H, J =

[Example 33]

Synthesis of 3- (hydroxymethyl) -2 - ((4-methoxyphenyl) sulfonyl) -1,3,4-trihydroisoquinoline

The reaction was carried out in the same manner as in Example 31 to yield 0.49 g (1.47 mmol, Yield 98%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 2.20 (t, 1H, J = 5.8Hz), 2.63-2.77 (m, 2H), 3.47-3.58 (m, 1H), 3.59-3.67 (m, 1H) 2H), 6.84 (d, 2H, J = 7.1 Hz), 6.99-7.06 (m, 2H) 7.09-7.14 (m, 2H), 7.68 (d, 2H, J = 7.1 Hz)

[Example 34]

Synthesis of 1 - ((4-methoxyphenyl) sulfonyl) piperidin-3-ol

The reaction was carried out in the same manner as in Example 31 to obtain 2.70 g (10 mmol, Yield: 100%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.36-1.47 (m, 1H), 1.64-1.93 (m, 3H), 2.01 (bs, 1H), 2.64-2.84 (d, 2H, J = 8.2 Hz), 7.71 (d, 2H, J = , J = 8.9 Hz)

[Example 35]

Synthesis of 2 - ((2-naphthyl) sulfonyl) -3- (hydroxymethyl) -1,3,4-trihydroisoquinoline

The reaction was carried out in the same manner as in Example 31 to give the title compound (336 mg, yield: 54%) as a pale yellow foamy solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 6.90-8.36 (m, 11H), 4.70 (d, 1Ha, J = 16.0Hz), 4.44 (d, 1Hb, J = 16.0Hz), 4.25-4.30 (m 2H), 2.10-2.14 (m, 1 H), < RTI ID = 0.0 &

[Example 36]

Synthesis of 4 - (((1 - ((4-methylphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to yield 186 mg (Yield: 65%) of the title compound as a white foamy solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.63-7.66 (m, 4H), 7.43 (d, 2H, J = 8.1Hz), 7.33 (d, 2H, J = 8.1Hz), 4.54 (s, 2H 2H), 3.36 (d, 2H, J = 1.1 Hz), 2.44 (s, 3H), 2.29-2.50 (m, 2H), 1.06-2.05

[Example 37]

Synthesis of 4 - (((1- (benzylsulfonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 137 mg (yield: 48%) of the title compound as a colorless liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.32-7.66 (m, 9H), 4.51 (s, 2H), 4.20 (s, 2H), 3.39-3.59 (m, 2H), 3.32-3.35 (m, 2H), 2.58-2.71 (m, 2H), 1.25-1.95 (M, 5H)

[Example 38]

Synthesis of 4 - (((1- (R) - (3-cyclohexyl) -2 - ((methylsulfonyl) amino) propanoyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 56 mg (yield: 100%) of the title compound as a pale yellow liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.41-7.66 (m, 4H), 4.51 (s, 2H), 4.32-4.45 (m, 1H), 4.64-3.80 (m, 2H), 3.36-3.49 ( m, 2H), 2.57-3.18 (m, 5H), 0.72-1.98 (m, 18H)

[Example 39]

Synthesis of 4 - (((1 - ((2-naphthyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to obtain 225 mg (yield: 71%) of the title compound as a white foamy solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.39-8.34 (m, 11H), 4.52 (s, 2H), 3.56-3.71 (m, 2H), 3.37 (d, 2H, J = 6.0Hz), 2.38 -2.56 (m, 2H), 1.06 - 2.04 (m, 5H)

[Example 40]

Synthesis of 4 - (((1- (naphthylsulfonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

(Silica gel, eluent ethyl acetate: n-hexane = 1: 2) to obtain 216 mg (yield: 69%) of the title compound as a white foamy solid by carrying out the reaction in the same manner as in Example 31. To obtain 242 mg (yield 34%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.33-8.74 (m, 11H), 4.40 (d, 2H, J = 6.0Hz), 3.56-3.72 (m, 2H), 3.31 (d, 2H, J = 3.5 Hz), 2.61-2.83 (m, 2H), 1.17-2.04 (m, 5H)

[Example 41]

Synthesis of 4 - (((1- (phenylcarbonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 131 mg (yield: 70%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , ppm)?: 7.15-7.66 (m, 9H), 4.44-4.59 (m, 3H), 3.64-3.87 1.92 (m, 5 H)

[Example 42]

Synthesis of 4 - (((1 - ((2-naphthyl) carbonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 154 mg (yield: 71%) of the title compound as a white foamy solid.

¹ H-NMR (CDCl ₃ , ppm)?: 7.01-7.89 (m, 1H), 4.28-4.67 (m, 3H), 3.72-3.99 2.02 (m, 5 H)

[Example 43]

Synthesis of 4 - (((1- (benzylsulfonyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 187 mg (yield: 64%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.33-7.65 (m, 9H), 4.53 (s, 2H), 4.27 (s, 2H), 3.81 (bs, 1H), 3.44-3.49 (m, 1Ha) , 3.29-3.35 (m, 1H), 3.15-3.25 (m, 2H), 1.81-1.89 (m, 4H)

[Example 44]

Synthesis of 4 - (((1 - ((4-nitrophenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give the title compound 1.2g (yield: 77%).

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.14-1.18 (1H, m), 1.66-1.77 (3H, m), 2.05-2.09 (1H, m), 2.42-2.58 (2H, m), 3.39- (2H, m), 7.46-7.69 (2H, m), 7.46-7.69 8.38-8.43 (2H, m)

[Example 45]

Yl) carbonyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarbamoylcarbamoyl chloride Synthesis of nitrile

The reaction was carried out in the same manner as in Example 31 to give 140 mg (yield: 80%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.84-2.01 (8H, m), 2.77 (1H, s), 2.87 (2H, s), 3.32-3.64 (4H, m), 4.17-4.20 (1H, m), 4.48-4.51 (3H, m), 7.33-7.38 (2H, m), 7.55-7.61 (2H, m)

[Example 46]

Synthesis of 4 - (((1- (S) - (3-phenylpropanoyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 240 mg (yield: 87%) of the title compound.

H-NMR ¹ (CDCl _3, ppm) δ: 1.78-1.91 (4H, m), 2.47-2.52 (2H, m), 2.87-2.92 (2H, m), 3.21-3.26 (2H, m), 3.42- (1H, m), 3.47 (1H, m), 3.59-3.63 (1H, m), 4.23 7.50-7.56 (2H, m)

[Example 47]

Synthesis of N- (2- (3 - ((4-cyanophenyl) methoxy) methyl) piperidyl) -2-oxoethyl) (2-naphthyl) formamide

The reaction was carried out in the same manner as in Example 31 to give 0.126 g (0.29 mmol, Yield: 84%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.30-1.68 (m, 2H), 1.71-1.99 (m, 3H), 2.72 (t, 0.5H, J = 10.0Hz), 2.91-3.17 (m, 1.5 H), 3.33-3.47 (m, 2H), 3.68-3.84 (m, 1H), 4.22-4.36 (m, 2.5H), 4.48-4.61 (m, 2.5H), 7.41-7.68 7.82-7.97 (m, 4 H), 8.38 (s, 1 H)

[Example 48]

Synthesis of 4 - (((1- (2 - ((4-methoxyphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to obtain 0.209 g (0.46 mmol, Yield: 91%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.32-1.47 (m, 2H), 1.66-1.87 (m, 3H), 2.57 (t, 0.5H, J = 10.0Hz), 2.86-2.99 3H), 3.99 (d, 0.5H, J = 14.0 Hz, H), 3.25-3.39 (m, 2H), 3.49 2H, J = 7.4 Hz), 7.42 (dd, 2H, < RTI ID = 0.0 > J = 3.7 Hz, 8.1 Hz), 7.65 (t, 2H, J = 9.3 Hz), 7.80 (t, 2H, J = 8.1 Hz)

[Example 49]

Synthesis of 4 - (((1- (2 - ((4-methylphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.129 g (0.29 mmol, Yield: 77%) of the title compound.

MS (ESI) m / e: 442 (M + H) +, 464 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.32-1.43 (m, 2H), 1.62-1.90 (m, 3H), 2.41 (s, 3H), 2.60 (t, 0.5H, J = 11.0Hz), 2H), 3.49 (t, 1H, J = 12.0 Hz), 3.68-3.81 (m, 2H), 4.01 (bd, 0.5H), 4.34 2H), 7.62-7.77 (m, 4H), 7.29-7.44 (m, 2H)

[Example 50]

Synthesis of 3 - (((1- (2 - ((2-naphthyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.265 g (0.55 mmol, Yield: 87%) of the title compound.

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.21-1.41 (m, 3H), 1.64-1.83 (m, 2H), 2.57 (t, 0.5H, J = 13.0Hz), 2.89 (bs, 1.5H) , 3.21-3.34 (m, 2H), 3.38-3.51 (m, 1H), 3.79 (bs, 2H), 3.98 (bd, 0.5H), 4.24 (d, 0.5H, J = 2H), 5.86 (bs, 1H), 7.41-7.69 (m, 6H), 7.82-8.01 (m, 4H), 8.43

[Example 51]

Synthesis of 3 - (((1- (2 - ((naphthylsulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.28 g (0.586 mmol, Yield: 89%) of the title compound.

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

¹ H-NMR (CDCl ₃ , ppm)?: 1.26-1.45 (m, 2H), 1.61-1.89 (m, 3H), 2.59 (t, 0.5H, J = 11.0Hz), 2.87-3.03 2H), 3.91-3.99 (m, 0.5H), 4.27 (d, 0.5H, J = 12.0 Hz), 4.45 (s, 2H) (M, 1H), 5.98 (s, 1H), 7.42-7.75 (m, 7H), 7.94 (d, 1H, J = 7.7Hz), 8.06-8.11 , 1H, J = 8.4 Hz)

[Example 52]

Synthesis of 3 - (((1- (2 - ((4-methoxyphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.292 g (0.638 mmol, Yield: 92%) of the title compound.

MS (ESI) m / e: 458 (M + H) +, 480 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.27-1.49 (m, 2H), 1.61-1.90 (m, 3H), 2.61 (t, 0.5H, J = 11.0Hz), 2.87-3.00 (m, 1.5 2H), 3.86 (s, 3H), 4.02 (d, 0.5H, J = 13.0 Hz), 3.27-3.40 (m, 2H) , 4.31 (d, 0.5H, J = 12.0 Hz), 4.45-4.57 (m, 2H), 5.66 (bs, 1H), 6.94-7.01 (m, 2H), 7.42-7.64 7.84 (m, 2H)

[Example 53]

Synthesis of 3 - (((1- (2 - ((4-methylphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.273 g (0.618 mmol, Yield: 86%) of the title compound.

MS (ESI) m / e: 442 (M + H) +, 464 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.29-1.50 (m, 2H), 1.62-1.91 (m, 3H), 2.41 (s, 3H), 2.61 (t, 0.5H, J = 12.0Hz), 2H), 3.47 (t, 1H, J = 13.0 Hz), 3.71-3.79 (m, 2H), 4.02 (d, 0.5H, J = 14.0 2H), 7.41-7.64 (m, 4H), 7.26-7.31 (m, 2H) 7.72-7.77 (m, 2H)

[Example 54]

Synthesis of 3 - (((1- (2 - ((4-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to yield 0.52 g (0.10 mmol, Yield: 82%) of the title compound.

MS (ESI) m / e: 473 (M + H) +, 495 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.31-1.50 (m, 2H), 1.63-1.91 (m, 3H), 2.61 (t, 0.5H, J = 12.0Hz), 2.89-3.03 (m, 1.5 (M, 3H), 3.82 (bs, 2H), 4.01 (d, 0.5H, J = 13.0 Hz), 4.31 (d, 0.5H, J = 11.0 Hz), 4.49 2H), 8.31-8.39 (m, 2H), 8.01-8. 11 (m,

[Example 55]

Synthesis of 3 - (((1- (2 - ((2-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.283 g (0.599 mmol, Yield: 89%) of the title compound.

MS (ESI) m / e: 473 (M + H) +, 495 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.31-1.51 (m, 2H), 1.61-1.94 (m, 3H), 2.59 (t, 0.5H, J = 11.0Hz), 2.89-3.09 (m, 1.5 J = 15.0 Hz), 3.99 (bs, 2.5H), 4.33 (d, 0.5H, J = 12.0Hz), 4.42-4.59 (m, 2H), 6.51 (bs, IH), 7.41-7.79 (m, 6H), 7.82-7.92 (m, IH), 8.06-8.14

[Example 56]

Synthesis of 4 - (((1- (2 - ((2-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.315 g (0.67 mmol, Yield: 73%) of the title compound.

MS (ESI) m / e: 473 (M + H) < ^{+ &}

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.17-1.35 (m, 2H), 1.42-1.87 (m, 3H), 2.51 (t, 0.5H, J = 12.0Hz), 2.82-2.99 (m, 1.5 2H), 3.49-3.62 (m, 1H), 3.89-3.39 (m, 2.5H), 4.28 (d, 0.5H, J = 14.0 Hz), 4.46 J = 19.6 Hz), 6.42 (bs, 1H), 7.35 (q, 2H, J = 7.8 Hz), 7.54-7.69 (m, 4H), 7.80 (d, 1H, J = 9.1 Hz), 7.99-8.08 m, 1H)

[Example 57]

Synthesis of 4 - (((1- (2 - ((3-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to yield 0.559 g (0.18 mmol, Yield: 77%) of the title compound.

MS (ESI) m / e: 473 (M + H) +, 495 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.19-1.37 (m, 2H), 1.65-1.83 (m, 3H), 2.51 (t, 0.5H, J = 13.0Hz), 2.82-2.98 (m, 1.5 2H), 3.87-3.97 (m, 0.5H), 4.21-4.31 (m, 0.5H) 2H, J = 7.8 Hz), 7.53-7.71 (m, 3H), 8.14 (d, (d, 1H, J = 6.6 Hz), 8.63 (d,

[Example 58]

Synthesis of 4 - (((1- (2 - ((naphthylsulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to give 0.284 g (0.59 mmol, Yield: 99%) of the title compound.

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.22-1.40 (m, 2H), 1.55-1.79 (m, 3H), 2.50 (t, 0.5H, J = 13.0Hz), 2.78-2.97 (m, 1.5 H), 3.18-3.43 (m, 3H), 3.66-3.74 (m, 2H), 3.87 (d, 0.5H, J = 14.0Hz), 4.22 2H), 5.92 (bs, 1H), 7.29-7.36 (m, 2H), 7.39-7.70 (m, 5H), 7.87 (d, 1H, J = 7.8Hz), 8.00 (Dd, 1H, J = 8.5 Hz, 16.0 Hz), 8.64 (d, 1H, J = 8.6 Hz)

[Example 59]

Synthesis of 4 - (((1- (2 - ((2-naphthylsulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 31 to obtain 0.278 g (0.58 mmol, Yield: 97%) of the title compound.

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.19-1.38 (m, 2H), 1.54-1.76 (m, 3H), 2.47 (t, 0.5H, J = 13.0Hz), 2.79-2.91 (m, 1.5 2H), 3.13-3.27 (m, 2H), 3.31-3.47 (m, 1H), 3.69-3.79 (m, 2H), 3.89 (d, 0.5H, J = 14.0Hz) J = 13.0 Hz), 4.34-4.49 (m, 2H), 5.79 (bs, IH), 7.31 (d, 2H, J = 6.8 Hz), 7.51-7.62 (m, 4H), 7.73-7.92 ), 8.36 (d, IH, J = 6.2 Hz)

[Example 60]

Synthesis of 4 - (((1 - ((4-methoxyphenyl) sulfonyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

(1.2 mmol) of 60% sodium hydride was added to a solution of 0.27 g (0.95 mmol) of 2-hydroxymethyl-1- (4-methoxybenzenesulfonyl) piperidine in 2 ml of dimethylsulfoxide, Lt; / RTI >

A solution of 0.20 g (1 mmol) of 4-cyanobenzyl bromide in 1 ml of tetrahydrofuran and 1 ml of dimethylsulfoxide was cooled in an ice-water bath and the above-prepared mixture was slowly added.

The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was extracted with dichloromethane and water and the organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica eluting with n-hexane: ethyl acetate 2: 1 to yield 0.17 g (0.42 mmol, 45% yield) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.19-1.37 (m, 1H), 1.39-1.56 (m, 4H), 1.74-1.80 (m, 1H), 2.96 (t, 1H, J = 11.3Hz) (D, 2H, J = 6.8 Hz), 3.72 (d, 1H, J = 11.0 Hz), 3.86 (s, 3H), 4.30 (bs, 2H, J = 8.9 Hz), 7.40 (d, 2H, J = 8.2 Hz), 7.63

[Example 61]

Synthesis of 4 - (((1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 60 to give 0.09 g (0.22 mmol, Yield: 24%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.02-1.17 (m, 1H), 1.60-1.78 (m, 3H), 2.05 (bs, 1H), 2.32 (t, 1H, J = 10.3Hz), 2.46 (d, 1H, J = 7.1, 11.1 Hz), 3.88 (s, 1H, J = 10.3 Hz), 3.38 (d, 2H, J = 7.1 Hz), 3.44-3.61 (D, 2H, J = 8.3 Hz), 7.70 (d, 2H, J = 2H), J = 8.9 Hz)

[Example 62]

Synthesis of 4 - (((2 - ((4-methoxyphenyl) sulfonyl) -3-1,2,3,4-tetrahydroisoquinolyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 60 to give 0.08 g (0.18 mmol, Yield: 12%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 2.74-2.90 (m, 2H), 3.34 (t, 1H, J = 8.7Hz), 3.55-3.61 (m, 1H), 3.83 (s, 3H), 4.35 2H, J = 8.9Hz), 7.01-7.07 (m, 2H), 7.12-7.42 (m, 1H), 4.40 (ABq, 2H, J = 15.5Hz) J = 8.3 Hz), 7.72 (d, 2H, J = 8.9 Hz), 7.17 (d, 2H, J =

[Example 63]

Synthesis of 4 - ((1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyloxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 60 to give 0.14 g (0.36 mmol, Yield: 36%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.54-1.67 (m, 1H), 1.79-1.98 (m, 3H), 2.47-2.58 (m, 2H), 3.32-3.41 2H), 3.65 (s, 3H), 4.63 (ABq, 2H, J = 12.8 Hz), 6.99 (d, 2H, J = 8.9 Hz), 7.44 7.63-7.71 (m, 4H)

[Example 64]

Synthesis of t-butyl 3 - (((4-cyanophenyl) methoxy) methyl) piperidine carboxylate

The reaction was carried out in the same manner as in Example 60 to give 40 g (0.186 mol) of 1- (t-butoxycarbonyl) -3- (±) - (hydroxymethyl) piperidine to obtain 9 g of a light yellow compound .

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.63 (d, 2H, J = 8.2Hz), 7.44 (d, 2H, J = 8.0Hz), 4.54 (s, 2H), 3.86-4.02 (m, 2H ), 3.37 (dd, 2H), 2.58-2.87 (m, 2H), 1.46 (s, 9H), 1.24-1.85

[Example 65]

Synthesis of 4 - (((2- (2-naphthylsulfonyl) -3-1,2,3,4-tetrahydroisoquinolyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 60 to give 47 mg (yield: 11%) of a pale yellow foamy solid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.01-8.39 (m, 1H), 4.46 (s, 2H), 4.35-4.65 (m, 3H), 3.57-3.62 (m, 1Ha), 3.34-3.40 ( m, 1H), 2.82-2.84 (m, 2H)

[Example 66]

Synthesis of t-butyl 2 - (((4-cyanophenyl) methoxy) methyl) pyrrolidinecarboxylate

49.71 g (0.247 mol) of (S) -1- (t-butoxycarbonyl) -2-pyrrolidinemethanol was dissolved in 150 ml of DMSO, 10.38 g (0.259 mol) of sodium hydride (60% in mineral oil) And the mixture was stirred for 30 minutes. 49.41 g (0.250 mol) of 4-cyanobenzyl bromide was dissolved in 150 ml of DMSO, and the mixture was added dropwise over 30 minutes, followed by stirring at room temperature for 5 hours. Water (1 L) was added to the reaction solution, extracted with dichloromethane (400 ml × 3 times), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on silica eluting with ethyl acetate: n-hexane = 1: 3 to obtain 18 g (0.0570 mol) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.46 (9H, s), 1.78-1.98 (4H, m), 3.37 (2H, brs), 3.51-3.66 (2H, m), 3.94-4.04 (1H, m), 4.60 (2H, s), 7.39-7.46 (2H, m), 7.64-7.67 (2H, m)

[Example 67]

Synthesis of t-butyl 3 - (((3-cyanophenyl) methoxy) methyl) piperidinecarboxylate

The reaction was carried out in the same manner as in Example 60 to obtain 9.80 g (0.030 mol, yield: 90%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.21-1.34 (m, 1H), 1.16 (s, 10H), 1.59-1.72 1H), 2.79-2.91 (m, 1H), 3.37 (d, 2H, J = 6.5 Hz), 3.88 7.45 (t, 1H, J = 7.7 Hz), 7.56-7.66 (m, 3H)

[Example 68]

Synthesis of t-butyl 2 - (((3-cyanophenyl) methoxy) methyl) piperidine carboxylate

The reaction was carried out in the same manner as in Example 60 to give 7.39 g (0.022 mol, yield: 45%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.36-1.53 (m, 1H), 1.54-1.70 (m, 3H), 1.72-1.83 (m, 1H), 2.75 (t, 1H, J = 11.0Hz) (M, 2H), 3.50-3.69 (m, 2H), 4.01 (d, 1H, J = 12.0 Hz), 4.44-4.66 (m, 3H), 7.42-7.49 (s, 1 H)

[Example 69]

Synthesis of t-butyl 2 - (((4-cyanophenyl) methoxy) methyl) piperidine carboxylate

The reaction was carried out in the same manner as in Example 60 to give 19.10 g (0.058 mol, yield: 58%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.44 (bs, 1H), 1.56-1.70 (m, 3H), 1.77 (d, 1H, 11.4Hz), 2.75 (t, 1H, 12.6Hz), 3.53- 2H, J = 8.1 Hz), 3.65 (m, 2H), 3.99 (d, 1H, J = 13.1 Hz), 4.48 (bs, , 7.63 (d, 2H, J = 8.2 Hz)

[Example 70]

Synthesis of 4 - (((1 - ((2-nitrophenyl) methyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

0.27 g (1.0 mmol) of 3- (4-cyanobenzyloxymethyl) piperidine hydrochloride and 0.43 g (2 mmol) of 2-nitrobenzylbromide were suspended in 10 ml of methanol and 0.3 ml (2.16 mmol) of triethylamine . The reaction mixture was stirred for 5 hours 30 minutes and concentrated under reduced pressure. A solution obtained by dissolving 0.1 g of sodium hydroxide in 50 ml of water was added to the residue and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with n-hexane: ethyl acetate 2: 1 to yield 0.29 g (0.79 mmol, Yield 79%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.44-1.72 (m, 4H), 1.87-2.19 (m, 3H), 2.56 (bs, 1H), 2.71 (d, 1H, J = 9.2Hz), 3.36 (d, 2H, J = 6.0 Hz), 3.75 (bs, 2H), 4.51 (s, 2H), 7.35-7.40 (m, 3H), 7.49-7.63 = 8.2 Hz)

[Example 71]

Synthesis of 4 - (((1- (2 - ((4-methoxyphenyl) methyl) amino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

A solution of 0.252 g (0.778 mol) of 2- (4-cyanobenzyloxymethyl) -1-glycylpiperidine hydrochloride in 5 ml of methanol was cooled in an ice-water bath. (0.778 mmol) of 4-methoxybenzyl chloride and 0.27 ml (1.945 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was extracted with dichloromethane and saturated sodium bicarbonate solution. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Kiselgel 60, flow-through chloroform: methanol = 15: 1) to obtain 0.033 g (0.08 mmol, Yield: 10%) of the target compound.

MS (ESI) m / e: 408 (M + H) < ^{+ &}

¹ H-NMR (CDCl ₃ , ppm)?: 1.21-1.92 (m, 6H), 2.59 (bs, 0.5H), 3.02 (bs, 5H), 3.32-3.92 (m, 9.5H) 2H, J = 8.2Hz), 4.41-4.67 (m, 2.5H), 4.99 (bs, 0.5H), 6.77-6.91 )

[Example 72]

Synthesis of 4 - (((1 - ((3-nitrophenyl) methyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 70 to give 0.22 g (0.60 mmol, Yield: 60%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.56-1.79 (m, 4H), 1.89-2.15 (m, 3H), 2.74 (bs, 1H), 2.87 (bs, 1H), 3.38 (d, 2H, J = 5.9 Hz), 3.58 (bs, 2H), 4.52 (s, 2H), 7.39 (d, 2H, J = 8.2 Hz), 7.48 J = 8.3 Hz), 7.67 (bs, 1H), 8.11 (d,

[Example 73]

Synthesis of 4 - (((1- (2- (benzylamino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 70 to give 0.032 g (0.085 mmol, Yield: 15%) of the title compound.

MS (ESI) m / e: 478 (M + H) < ^{+ &}

¹ H-NMR (CDCl ₃ , ppm)?: 1.21-1.92 (m, 6H), 2.59 (bs, 0.5H), 3.01 (bs, 0.5H), 3.33-3.89 2H, J = 8.1 Hz), 4.39-4.68 (m, 2.5H), 4.99 (bs, 0.5H), 7.17-7.47

[Example 74]

Amino] propanoyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile The title compound was synthesized in the same manner as in Synthesis Example 1, except that 1 - (((1- (2- (S) -

The reaction was carried out in the same manner as in Example 70 to give 0.722 g (1.65 mmol, Yield: 63%) of the title compound.

MS (ESI) m / e: 437 (M + H) < ^{+ &}

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.17 (d, 1H, J = 6.9Hz), 1.25 (d, 2H, J = 7.0Hz), 1.34-1.53 (m, 2H), 1.57-1.94 (m , 4H), 2.63 (t, 0.5H, J = 11.0 Hz), 3.06 (t, 0.5H, J = 11.0 Hz), 3.48-3.93 (m, 6H), 4.11 2H), 5.08 (bs, 0.5H), 7.33-7.48 (m, 3H), 7.53-7.64 (m, 3H), 8.11-8.19

[Example 75]

Amino] propanoyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile The title compound was synthesized in the same manner as in (1)

The reaction was carried out in the same manner as in Example 70 to give 0.779 g (1.78 mmol, Yield: 66%) of the title compound.

MS (ESI) m / e: 437 (M + H) < ^{+ &}

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.17 (d, 1H, J = 6.9㎐), 1.27 (d, 2H, J = 7.1㎐), 1.32-1.51 (m, 2H), 1.54-1.98 (m , 4H), 2.64 (t, 0.5H, J = 11.0 Hz), 3.06 (q, 0.5H, J = 11.0 Hz), 3.37-3.94 (m, 6H), 4.12 2H), 5.01-5.20 (m, 0.5H), 7.33-7.75 (m, 6H), 8.03-8.22 (m, 2H)

[Example 76]

Synthesis of 4 - (((1- (2- (bis (2-naphthylmethyl) amino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 70 to give 0.172 g (0.30 mmol, Yield: 39%) of the title compound.

MS (ESI) m / e: 467 (M) <^+> , 468 (M + H) < ⁺

¹ H-NMR (CDCl ₃ , ppm)?: 1.26-1.40 (m, 2H), 1.41-1.80 (m, 4H), 2.50 (bt, 0.5H), 2.80-2.94 2H), 3.94 (d, 0.5H, J = 13.1 Hz), 4.11 (m, 2H), 3.51-3.73 (d, 1H, J = 13.2 Hz), 4.21 (bs, 0.5H), 4.47 (q, 2H, J = 16.3 Hz), 4.97 , 7.28 (bs, 1H), 7.41-7.56 (m, 8H), 7.71-7.86 (m, 8H)

[Example 77]

Synthesis of 4 - (((1- (2 - ((cyclohexylmethyl) amino) acetyl) -2-piperidyl) methoxy) -methyl) benzenecarbonitrile

A mixture of 0.15 g (0.54 mmol) of 2- (4-cyanobenzyloxymethyl) -1-glycylpiperidine and 0.087 ml (0.62 mmol) of (bromomethyl) cyclohexane was left at 80-90 ° C for 1 hour did. The mixture was cooled and subjected to column chromatography (Kiselgel 60, mobile phase MC: MeOH = 9: 1) to obtain 0.029 g (0.076 mmol, yield 15%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 0.82-1.01 (m, 2H), 1.09-1.32 (m, 3H), 1.35-1.52 (m, 3H), 1.54-1.87 bs, 2H), 2.59 (bs, 0.5H), 3.05 (bs, 0.5H), 3.34-3.78 (m, 4.5H), 4.56 (bs, 2.5H), 4.98 , &Lt; / RTI &gt; 2H), 7.63 (d, 2H, J =

[Example 78]

Synthesis of ethyl 2 - ((2-3 ((4-cyanophenyl) methoxy) methyl) piperidyl) -1- (cyclohexylmethyl) -2-oxoethyl) amino) acetate

The reaction was carried out in the same manner as in Example 77 to give 83 mg (yield: 27%) of the title compound as a pale yellow liquid.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 7.42-7.67 (m, 4H), 4.54 (s, 2H), 4.14-4.18 (m, 2H), 3.64-3.77 (m, 4H), 3.40 (d, 2H, J = 6.0 Hz), 3.15-3.21 (m, 1H), 2.55-3.07 (m, 2H), 0.77-1.85

[Example 79]

Synthesis of 4 - (((1 - ((2-aminophenyl) methyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

0.2 g (0.79 mmol) of 3- (4-cyanobenzyloxymethyl-1- (2-nitrobenzyl) piperidine was dissolved in 15 ml of ethyl acetate and 10 ml of methanol and 0.15 g of 10% palladium on charcoal was added (0.63 mmol, yield 79%) of the title compound was obtained as a white solid from &lt; RTI ID = 0.0 &gt; .

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.43-1.59 (m, 1H), 1.59-1.86 (m, 4H), 1.86-2.00 (m, 2H), 3.73 (bs, 1H), 2.87 (d, 1H, J = 10.5 Hz), 3.27-3.39 (m, 2H), 3.41-3.55 (m, 2H), 4.50 (s, 2H), 6.62-6.69 J = 8.3 Hz), 7.62 (d, 2H, J = 8.3 Hz), 7.02-7.13 (m,

[Example 80]

Synthesis of 4 - (((1 - ((3-aminophenyl) methyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 79 to give 0.17 g (0.51 mmol, Yield: 84%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.56-1.87 (m, 5H), 1.93-2.09 (m, 2H), 2.78 2H), 7.09 (m, 2H), 4.51 (s, 2H), 6.59 (d, 1H, J = 8.1 Hz), 6.69 J = 7.9 Hz), 7.39 (d, 2H, J = 8.1 Hz), 7.62 (d, 2H, J = 8.2 Hz)

[Example 81]

Synthesis of 3 - (((1- (2 - ((4-aminophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 79 to give 0.399 g (0.90 mmol, yield quantitative) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.27-1.48 (m, 2H), 1.66-1.91 (m, 3H), 2.61 (t, 0.5H, J = 12.0㎐), 2.87-2.99 (m, 1.5 2H), 3.72 (b, 2H), 4.02 (d, 0.5H, J = 14.5 Hz), 4.12 (bs, 2H) , 4.31 (d, 0.5H, J = 13.0 Hz), 4.45-4.57 (m, 2H), 5.59 (bs, 1H), 6.62-6.70 (m, 2H), 7.41-7.68

[Example 82]

Synthesis of 3 - (((1- (2 - ((2-aminophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 79 to give 0.142 g (0.32 mmol, Yield: 84%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.29-1.46 (m, 2H), 1.67-1.91 (m, 3H), 2.61 (t, 0.5H, J = 12.0㎐), 2.87-2.99 (m, 1.5 2H), 4.01 (d, 0.5H, J = 14.0 Hz), 4.31 (d, 2H), 3.26-3.39 1H, J = 13.0 Hz), 4.44-4.52 (m, 2H), 4.93 (bs, 2H), 6.01 (bs, 1H), 6.72-6.82 ㎐), 7.41-7.71 (m, 5H)

[Example 83]

Amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile was synthesized in the same manner as in Synthesis Example 1,

The reaction was carried out in the same manner as in Example 79 to give 0.128 g (0.29 mmol, Yield: 72%) of the title compound.

MS (ESI) m / e: 443 (M + H) +, 465 (M + Na) +

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.21-1.37 (m, 2H), 1.62-1.81 (m, 3H), 2.52 (t, 0.5H, J = 12.0㎐), 2.80-2.93 (m, 1.5 H), 3.27 (bs, 2H), 3.35-3.47 (m, 1H), 3.65 (bs, 2H), 3.87-3.99 (m, 0.5H), 4.20-4.31 (m, 2H), 4.86 (bs, 2H), 5.90 (bs, 1H), 6.63-6.75 (m, 2H), 7.24 (t, 1H, J = 8.8Hz), 7.31-7.39 -7.64 (m, 3 H)

[Example 84]

Amino] acetyl) -3-piperidyl) methoxy) methyl) benzenecarbonitrile The title compound was synthesized in the same manner as in Synthesis Example 1,

The reaction was carried out in the same manner as in Example 79 to yield 0.31 g (0.70 mmol, Yield: 87%) of the title compound.

MS (ESI) m / e: 443 (M + H) +, 465 (M + Na) +

¹ H-NMR (CDCl ₃ , ppm)?: 1.19-1.33 (m, 2H), 1.66-1.82 (m, 3H), 2.55 (t, 0.5H, J = 13.0 Hz), 2.81-2.97 (M, 2H), 3.82 (bs, 2H), 3.96 (d, 0.5H, J = 14.0 Hz), 3.21-3.22 (m, 2H), 3.33-3.47 1H, J = 6.1 Hz), 7.04-7.23 (m, 3H), 7.31 (d, 2H, J = 7.38 (m, 2H), 7.58 (t, 2H, J = 8.9 Hz)

[Example 85]

Synthesis of 4 - (((1- (2- (2 - ((methylsulfonyl) amino) phenyl) ethanoyl) 3-piperidyl) methyloxy) methyl) benzenecarbonitrile

120 mg (yield 86%) of 1- (2-amidophenylacetyl) -3- (4-cyanobenzyloxymethyl) piperidine was obtained in the same manner as in Example 79, 112 mg (yield 77%) of the title compound was obtained in the same manner.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.25-1.46 (2H, m), 1.66-1.85 (3H, m), 2.67-2.72 (½H, m), 2.82-2.91 (½H, m), 3.08 ( (2H, m), 3.98-4.04 (2H, m), 4.15-3.15 (2H, m) M), 7.42-7.19 (2H, m), 7.28-7.31 (1H, m), 4.52 (1H, 7.51 (2H, m), 7.54-7.56 (1H, m), 7.62-7.71 (2H, m), 9.67

[Example 86]

Methyl) benzenecarbonitrile and 4 - (((1 - ((2- (2 - ((methylsulfonyl) (Methylsulfonyl) amino) phenyl) methyl) -3-piperidyl) methyloxy) methyl) benzenecarbonitrile

0.21 g (0.63 mmol) of 1- (2-aminobenzyl) -3- (4-cyanobenzyloxymethyl) piperidine was dissolved in 4 ml of pyridine and the solution was cooled in an ice-water bath. 0.1 ml (1.3 mmol) of methanesulfonyl chloride was added to the cooled solution, and the mixture was stirred at room temperature for 6 hours. 5 ml of methanol was added and stirred for 10 minutes. The solution was concentrated under reduced pressure and the residue was extracted with dichloromethane and diluted potassium carbonate solution. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (Kiselgel 60, eluent n-hexane: ethyl acetate = 2: 1) to give 3- (4-cyanobenzyloxymethyl) -1- (2-dimethanesulfonamidobenzyl) piperidine (0.22 mmol, yield 35%) of 0.10 g (0.20 mmol, Yield: 32%) of 3- (4-cyanobenzyloxymethyl) Respectively.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.42-1.68 (m, 3H), 1.69-1.82 (m, 2H), 1.82-2.03 (m, 2H), 2.77 (bs, 1H), 2.85 (d, (S, 2H), 3.48 (s, 2H), 3.48 (d, 1H, J = 2H), 7.30-7.45 (m, 5H), 7.50 (d, 1H, J = 6.8 Hz), 7.61

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.18 (bs, 1H), 1.56-1.71 (m, 3H), 1.97-2.21 (m, 3H), 2.72 (bs, 1H), 2.84 (bs, 1H) 2H), 3.30 (d, 2H, J = 5.0 Hz), 3.02 (s, 3H) J = 8.0 Hz), 7.38 (d, 2H, J = 8.2 Hz), 7.50 (d,

[Example 87]

Methylphenyl) sulfonyl) amino) ethanoyl) -3-piperidyl) methyloxy) methyl) benzenecarbonitrile was synthesized in the same manner as in Synthesis Example 1,

The reaction was carried out in the same manner as in Example 86 to obtain 0.20 g (0.38 mmol, Yield: 96%) of the title compound.

MS (ESI) m / e: 521 (M + H) &lt; ^{+ &}

¹ H-NMR (CDCl ₃ , ppm)?: 1.21-1.33 (m, 2H), 1.61-1.84 (m, 3H), 2.53 (t, 0.5H, J = 13.0 Hz), 2.80-2.94 2H), 3.96 (d, 0.5H, J = 14.0 Hz), 4.28 (d, 2H), 3.01 (t, 3H, J = 4.0 Hz), 3.21-3.33 (M, 4H), 7.52-7.64 (m, 4H), 7.51 (bs, 4H)

[Example 88]

Synthesis of 3 - (((1- (2 - ((4- ((methylsulfonyl) amino) phenyl) sulfonyl) amino) ethanoyl) -3-piperidyl) methyloxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 86 to give 0.324 g (0.62 mmol, Yield 92%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} ppm) δ: 1.26-1.49 (m, 2H), 1.63-1.91 (m, 3H), 2.57 (t, 0.5H, J = 12.0㎐), 2.88-3.02 (m, 1.5 H), 3.10 (s, 3H), 3.27-3.41 (m, 2H), 3.54 (t, 1H, J = 12.0 Hz), 3.77-3.91 2H), 5.82 (q, 1H, J = 5.5 Hz), 7.19-7.34 (m, 2H), 7.41-7.65 m, 4H), 7.82 (dd, 2H, J = 2.0 Hz, 8.8 Hz)

[Example 89]

Synthesis of 4 - (((1 - ((3 - ((methylsulfonyl) amino) phenyl) methyl) -3-piperidyl) methyloxy) methyl) benzenecarbonitrile

The reaction was carried out in the same manner as in Example 86 to give 0.16 g (0.39 mmol, Yield: 76%) of the title compound.

¹ H-NMR (CDCl ₃ , ppm)?: 1.11 (bs, 1H), 1.66-1.81 (m, 3H), 1.91-2.17 (m, 3H), 2.84 (m, 2H), 3.58 (q, 2H, J = 11.8 Hz), 4.52 (s, 2H), 7.16 (t, 2H, J = 6.9 Hz), 7.31 (t, 2H, J = 7.8 Hz), 7.40

[Example 90]

Synthesis of 4 - (((1 - ((4-methoxyphenyl) sulfonyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

0.15 g (0.37 mmol) of 2- (4-cyanobenzylsulfonyl) piperidine was dissolved in 7 ml of dichloromethane, 15 ml of a saturated hydrochloric acid ethanol solution was added, Lt; / RTI &gt; for 1 day. The reaction solution was concentrated to dryness under reduced pressure, and 20 ml of a saturated ammonia ethanol solution was added to the residue. The reaction solution was stirred at room temperature for 2 days and concentrated to dryness under reduced pressure. The residue was subjected to column chromatography (Fuji silisia DM1020, mobile phase ethyl acetate methanol 25%) to obtain 0.06 g (0.14 mmol, yield 39%) of the title compound.

MS (ESI) m / e: 418 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD, ppm)?: 1.19 (bs, 1H), 1.36-1.47 (m, 4H), 1.66 (d, 1H, J = 10.5 Hz) 2H), 3.50 (d, 2H, J = 7.0 Hz), 3.59 (d, 1H, J = 15.0 Hz), 3.75 (s, 3H), 4.13 (bs, 2H), 7.90 (d, 2H, J = 8.4 Hz), 7.60-7.67 (m, 4H)

[Example 91]

Synthesis of 4- (2- (1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyl) vinyl-benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 252 mg (yield 92%) of the title compound as a white solid.

MS (ESI) m / e: 400 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} , ppm) δ: 6.98-7.67 (m, 8H), 5.44-6.50 (m, 2H), 3.79 (s, 3H), 3.44-3.52 (m, 2H), 1.08-2.76 (m, 7H)

[Example 92]

Synthesis of 4 - (((1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.06 g (0.14 mmol, Yield: 64%) of the title compound.

MS (ESI) m / e: 418 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD, ppm)?: 1.94 (q, 1 H, J = 10.5 Hz), 1.42-1.67 (m, 3H), 1.84 (bs, 2H), 3.51 (d, 1H, J = 11.7 Hz), 3.78 (s, 3H), 4.44 (s, 2H) 7.01 (d, 2H, J = 9.0 Hz), 7.33 (d, 2H, J = 8.5 Hz), 7.56-7.64 (m, 4H)

[Example 93]

Synthesis of 4 - (((2 - ((4-methoxyphenyl) sulfonyl) -3-1,2,3,4- tetrahydroisoquinolyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.02 g (0.04 mmol, Yield: 24%) of the title compound.

MS (ESI) m / e: 466 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} , ppm) δ: 2.70 (d, 2H, J = 4.8㎐), 3.29 (d, 1H, J = 7.3㎐), 3.42 (t, 1H, J = 5.4㎐), 3.71 (s, 3H), 4.12-4.28 (m, 2.5H), 4.37-4.48 (m, 2.5H), 6.82 (d, 2H, J = ), 7.28 (d, 2H, J = 8.5 Hz), 7.58-7.61 (m, 4H)

[Example 94]

Synthesis of 4 - ((1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyloxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.11 g (0.27 mmol, Yield: 76%) of the title compound.

_{^{1 H-NMR (CD 3 OD}} , ppm) δ: 1.41-1.61 (m, 2H), 1.81-1.93 (m, 2H), 2.76 (t, 2H, J = 9.6㎐), 3.19 (bs, 1H), 2H), 3.40 (dd, 1H, J = 3.2, 11.2 Hz), 3.59 (bs, , 7.49 (d, 2H, J = 8.4 Hz), 7.70-7.77 (m, 4H)

[Example 95]

Synthesis of 4 - (((1 - ((2- (bis (methylsulfonyl) amino) phenyl) methyl-3-piperidyl) methyloxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.06 g (0.12 mmol, Yield: 59%) of the title compound.

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

^{1 H-NMR (DMSO-d} 6) δ: 1.01 (bs, 1H), 1.45 (bs, 1H), 1.63 (t, 2H, J = 14.7㎐), 1.78 (bs, 2H), 1.96 (t, 1H 2H, J = 11.6 Hz), 2.66 (d, 1H, J = 12.6 Hz), 2.80 (d, 1H, J = 6.8 Hz), 3.33 (bs, 2H) 2H), 4.45 (s, 2H), 6.80-7.22 (m, 3H), 7.30 (d, 2H, J = 8.1 Hz), 7.39-7.56

[Example 96]

Synthesis of 4 - (((1 - ((2 - ((methylsulfonyl) amino) phenyl) methyl) -3-piperidyl) methyloxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.07 g (0.16 mmol, yield 74%) of the title compound.

MS (ESI) m / e: 478 (M + H) +, 500 (M + Na) +

^{1 H-NMR (DMSO-d} 6) δ: 1.00-1.13 (m, 1H), 1.39-1.56 (m, 1H), 1.67 (d, 2H, J = 10.4㎐), 1.87 (bs, 2H), 2.04 (d, 1H, J = 7.3 Hz), 2.96 (s, 3H), 3.11-3.50 (m, 2H) 2H), 3.61 (s, 2H), 4.47 (s, 2H), 6.96 (t, 1H, J = 7.2 Hz), 7.20-7.25 (m, 2H), 7.31-7.35 , J = 8.2 Hz)

[Example 97]

Synthesis of 4 - (((1 - ((3 - ((methylsulfonyl) amino) phenyl) methyl) -3-piperidyl) methyloxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.11 g (0.26 mmol, Yield: 66%) of the title compound.

^{1 H-NMR (DMSO-d} 6) δ: 1.01 (m, 1H), 1.40-1.99 (m, 6H), 2.68 (d, 1H, J = 10.4㎐), 2.79 (bs, 1H), 2.81 (s 1H, J = 7.5 Hz), 6.97-7.03 (m, 2H), 7.16 (m, 2H) t, 1H, J = 7.7 Hz), 7.35 (d, 2H, J = 8.2 Hz), 7.76 (d, 2H, J =

[Example 98]

Synthesis of 4 - (((1- (S) - (3-phenylpropanoyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 180 mg (yield 74%) of the title compound.

MS (ESI) m / e: 366 (M + H) &lt; ^{+ &}

^{1 H-NMR (MeOH-d} 4) δ: 1.85-1.99 (4H, m), 2.60-2.65 (2H, m), 2.88-2.93 (2H, m), 3.32-3.39 (2H, m), 3.52- M), 7.40-7.48 (2H, m), 7.71-7.77 (2H, m), 3.63 (2H, m), 4.22 (1H, br s), 4.54-4.59 (2H, m), 7.15-7.27

[Example 99]

Synthesis of t-butyl 2 (R) - ((2- (S) - ((4-cyanophenyl) methoxy) methyl) pyrrolidinyl) carbonyl) pyrrolidinecarboxylate

The reaction was carried out in the same manner as in Example 90 to give 40 mg (yield 62%) of the title compound.

MS (ESI) m / e: 331 (M + 1) &lt; ^{+ &}

¹ H-NMR (MeOH-d ₄ )?: 1.55-1.69 (3H, m), 1.79-1.95 (5H, m), 2.63-2.67 M), 7.31-7.36 (2H, m), 7.61-7.66 (2H, m), &lt; RTI ID = )

[Example 100]

Pyrrolidin-2-yl) methoxy) methyl) benzene &lt; / RTI &gt; Synthesis of Vax amidine

The reaction was carried out in the same manner as in Example 90 to give 25 mg (yield 37%) of the title compound.

MS (ESI) m / e: 409 (M + H) &lt; ^{+ &}

^{1 H-NMR (MeOH-d} 4) δ: 1.79-1.94 (8H, m), 2.77 (1 1/5 H, s), 2.82 (1 4/5 H, s), 3.20-3.22 (2H, m ), 3.32-3.42 (4H, m), 3.52-3.55 (2H, m), 4.08-4.11 (? H, m), 4.34-4.36 (? H, m), 4.49-4.51 (2H, m), 7.61-7.66 (2H, m)

[Example 101]

Synthesis of 4 - (((1- (2- (2-nitrophenyl) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 45 mg (yield 71%) of the title compound.

¹ H-NMR (CDCl ₃ )?: 1.33-1.93 (5H, m), 2.88-2.92 (? H, m), 3.05-3.09 (? H, m), 3.28-3.35 (2H, m), 3.98-4.04 (2H, m), 4.19-4.31 (2H, m), 4.59-4.65 (2H, m), 7.40-7.57 (4H, m), 7.64-7.75 8.11-8.15 (1 H, m)

[Example 102]

Synthesis of 4 - (((1- (2- (2- (methylsulfonyl) amino) phenyl) ethanoyl) -3-piperidyl) methyloxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 98 mg (yield 84%) of the title compound.

^{1 H-NMR (MeOH-d} 4) δ: 1.32-1.51 (3H, m), 1.70-1.82 (2H, m), 2.79-2.86 (3H, m), 2.90-3.10 (1H, m), 3.33- (1H, m), 3.43 (3H, m), 3.78-3.97 (3H, m), 4.30-4.35 (1H, m), 4.50-4.61 ), 7.35-7.38 (1H, m), 7.47-7.50 (1H, m), 7.57-7.60 (1H, m), 7.77-7.80 (2H, m), 7.93-7.95

[Example 103]

Synthesis of 4 - (((1- (S) - (2 - ((phenylsulfonyl) amino) propanoyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 82 mg (yield 83%) of the title compound.

MS (ESI) m / e: 459 (M + 1) &lt; ^{+ &}

^{1 H-NMR (MeOH-d} 4) δ: 1.06-1.11 (3H, m), 1.18-1.23 (2H, m), 1.48-1.65 (3H, m), 2.29-2.50 (1H, m), 2.71- (1H, m), 2.89 (1H, m), 3.17-3.30 (2H, m), 3.68-4.05 (2H, m), 4.21-4.24 ). 7.61-7.73 (4 H, m)

[Example 104]

Synthesis of 4 - (((1 - ((4-nitrophenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 84 mg (yield 80%) of the title compound.

MS (ESI) m / e: 433 (M + 1) &lt; ⁺ & gt ^;

¹ H-NMR (MeOH-d ₄ )?: 1.11-1.14 (1H, m), 1.64-1.77 (3H, m), 1.97-2.01 (1H, m), 2.35-2.42 (1H, m), 2.57 (1H, m), 3.36-3.47 (2H, m), 3.58-3.62 (1H, m), 3.71-3.75 D, J = 8.7 Hz), 7.75 (2H, d, J =

[Example 105]

Pyrrolidin-2 (S) -yl) methoxy) methyl) benzenecarboxamide, which is used in the preparation of 4 - ((1- (3- (R) -1,2,3,4-tetrahydroisoquinolylcarbonyl) Synthesis of Dean

The reaction was carried out in the same manner as in Example 90 to give 47 mg (yield 85%) of the title compound as a white solid.

MS (ESI) m / e: 393 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 6.82-7.78 (m, 8H), 4.61 (d, 2H, J = 15.0 Hz), 4.25-4.50 (m, 1H), 4.01-4.06 (m, 2H). 3.51-3.83 (m, 5H), 2.84-3.01 (m, 2H), 1.92-2.15 (m, 4H)

[Example 106]

Pyrrolidine-2 (S) -yl) methoxy) methyl) benzenecarboxamide (S) - Synthesis of Dean

The reaction was carried out in the same manner as in Example 90 to give 31 mg (yield 82%) of the title compound as a white solid.

MS (ESI) m / e: 393 (M + H) &lt; ^{+ &}

_{1H-NMR (CD 3 OD)} δ: 6.91-7.67 (m, 8H), 4.51 (s, 2H), 4.11-4.25 (m, 1H), 3.44-3.95 (m, 7H), 2.71-2.75 (m, 2H), 1.88-1.97 (m, 4H)

[Example 107]

Synthesis of 4 - (((1- (benzylsulfonyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 134 mg (yield 71%) of the title compound as a white solid.

MS (ESI) m / e: 388 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.25-7.65 (m, 9H), 4.46 (s, 2H), 4.27 (d, 2H, J = 5.0Hz), 3.71 (bs, 1H), 3.11-3.40 ( m, 4H), 1.73-1.84 (m, 4H)

[Example 108]

Synthesis of 4 - (((1- (S) - (2-phenylacetyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 161 mg (yield 78%) of the title compound as a white solid.

MS (ESI) m / e: 352 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 7.09-7.65 (m, 9H), 4.44 (s, 2H), 4.16 (bs, 1H), 3.38-3.65 (m, 6H), 1.78-1.95 )

[Example 109]

Synthesis of 4 - (((1 - ((2-naphthyl) carbonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 144 mg (yield 91%) of the title compound as a white solid.

MS (ESI) m / e: 402 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 6.91-7.82 (m, 11H), 4.23-4.53 (m, 2H), 2.85-3.85 (m, 6H), 1.18-1.89 (m, 5HH)

[Example 110]

Synthesis of 4 - (((1- (phenylcarbonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 110 mg (yield 82%) of the title compound as a white solid.

MS (ESI) m / e: 352 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 7.14-7.67 (m, 9H), 4.32-4.51 (m, 2H), 2.79-3.77 (m, 6H), 1.18-1.89

[Example 111]

Synthesis of 4 - (((1- (naphthylmethyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 28 mg (yield 61%) of the title compound as a pale yellow solid.

MS (ESI) m / e: 388 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.24-8.20 (m, 11H), 4.34 (s, 2H), 3.80 (s, 2H), 3.21-3.29 (m, 2H), 2.72-2.87 (m, 2H ), 1.15-2.06 (m, 7H)

[Example 112]

Synthesis of 4 - (((1- (naphthylsulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 174 mg (yield 79%) of the title compound as a white solid.

MS (ESI) m / e: 438 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.26-8.63 (m, 1H), 4.29 (q, 2H, J = 2.0Hz), 3.44-3.63 (m, 2H), 3.11-3.23 (m, 2H), 2.44-2.75 (m, 2H), 1.03-1.79 (m, 5H)

[Example 113]

Synthesis of 4 - (((1 - ((2-naphthyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 172 mg (yield 74%) of the title compound as a white foamy solid.

MS (ESI) m / e: 438 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.46-8.39 (m, 11H), 4.56 (s, 2H), 3.58-3.76 (m, 2H), 3.32-3.45 (m, 2H), 2.33-2.59 (m , 2H), 1.05-2.02 (m, 5H)

[Example 114]

Synthesis of 4 - (((1- (R) - (3-cyclohexyl) -2 - ((methylsulfonyl) amino) propanoyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 22 mg (yield 41%) of the title compound as a pale yellow solid.

MS (ESI) m / e: 479 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.39-7.66 (m, 4H), 4.47 (s, 2H), 4.34-4.39 (m, 1H), 3.63-4.00 (m, 2H), 2.75 (d, 3H , J = 8.0 Hz), 2.55-3.21 (m, 2H), 0.68-1.80 (m, 18H)

[Example 115]

Ethyl) amino) - &lt; / RTI &gt; acetate and &lt; RTI ID = 0.0 &gt; 3-cyclohexylpropanoyl) -3-piperidyl) methoxy) methyl) benzenecarboxamide (hereinafter, Synthesis of amidine

The reaction was carried out in the same manner as in Example 90 to give A (20 mg) and B (21 mg).

MS (ESI) m / e: A 487 (M + H) &lt; ^{+ &}

B 458 (M + H) &lt; ⁺ & gt ^;

_{^{1 H-NMR (CD 3 OD}} ) δ: A 7.43-7.81 (m, 4H), 4.50 (s, 2H), 3.95-4.04 (m, 2H), 3.14-3.81 (m, 7H), 2.51-2.97 ( m, 2 H), 0.74 - 1.80 (m, 21 H); (M, 4H), 4.49 (s, 2H), 2.52-4.32 (m, 9H), 0.71-1.80

[Example 116]

Synthesis of 2 - ((2- (R) - (3 - ((4-amidinophenyl) methoxy) methyl) piperidyl) -1- (cyclohexylmethyl) -2-oxoethyl) amino) acetic acid

Methyl) piperidyl) -1- (cyclohexylmethyl) -2-oxo (2-oxoethyl) piperidine obtained in Example 115 Ethyl) amino) acetate was dissolved in 0.5 ml of EtOH, 1 ml of 2N NaOH was added, and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography on NH-DM1020 silica eluting with a solvent mixture of EA: MeOH = 1: 1 to give 5 mg (41% yield) of a pale yellow solid.

MS (ESI) m / e: 459 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.45-7.77 (m, 4H), 4.47-4.52 (m, 2H), 3.61-4.10 (m, 2H), 3.20 (s, 2H), 2.85-3.35 (m , &Lt; / RTI &gt; 4H), 0.72-1.95 (m, 18H)

[Example 117]

Synthesis of 4 - (((1 - ((R) - (+) - 2- amino-3-cyclohexylpropanoyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 27 mg (yield 47%) of the title compound as a white solid.

MS (ESI) m / e: 401 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.46-7.95 (m, 4H), 4.51 (s, 2H), 4.01-4.39 (m, 1H), 3.68-3.86 (m, 2H), 3.27-3.43 (m , 2H), 2.55-3.01 (m, 2H), 0.75-1.79 (m, 18H)

[Example 118]

Synthesis of 4 - (((1- (benzylsulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 89 mg (yield 64%) of the title compound as a white solid.

MS (ESI) m / e: 402 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.18-7.58 (m, 9H), 4.35 (s, 2H), 4.13 (s, 2H), 3.13-3.46 (m, 4H), 2.39-2.59 (m, 2H ), 0.99-1.72 (m, 5H)

[Example 119]

Synthesis of 4 - (((1 - ((4-methylphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 148 mg (yield 78%) of the title compound as a white solid.

MS (ESI) m / e: 402 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.11-7.66 (m, 8H), 4.45 (s, 2H), 3.21-3.54 (m, 4H), 2.34 (s, 3H), 2.11-2.32 (m, 2H ), 0.94-1.95 (m, 5H)

[Example 120]

Synthesis of 4 - (((1- (2-phenylsulfonyl) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 33 mg (yield 43%) of the title compound as a white solid.

MS (ESI) m / e: 430 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.30-7.78 (m, 9H), 4.73 (bs, 2H), 4.38-4.44 (m, 2H), 3.95-4.10 (m, 1Ha), 3.65-3.78 (m , 1H), 3.13-3.28 (m, 2H), 2.80-2.98 (m, 1H), 2.58-2.67

[Example 121]

Synthesis of 4 - (((1- (R) - ((1- (methylsulfonyl) pyrrolidin-2-yl) carbonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 109 mg (yield 71%) of the title compound as a white solid.

MS (ESI) m / e: 423 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.39-7.66 (m, 4H), 4.74 (bs, 1H), 4.48 (s, 2H), 3.90-4.37 (m, 2H), 3.33-3.42 (m, 2H ), 2.85 (s, 3H), 2.50-3.08 (m, 2H), 1.08-2.06 (m,

[Example 122]

Synthesis of 4 - (((1- (2-phenylacetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 214 mg (yield 86%) of the title compound as a pale yellow solid.

MS (ESI) m / e: 366 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.11-7.66 (m, 9H), 4.46 (s, 1Ha), 4.38 (s, 1Hb), 4.15-4.36 (m, 1Ha), 3.67-3.90 (m, 1Hb ), 3.16-3.29 (m, 2H), 2.58-3.05 (m, 2H), 1.09-1.67 (m, 5H)

[Example 123]

Synthesis of 4 - (((2- (2-naphthylsulfonyl) -3-1,2,3,4-tetrahydroisoquinolyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give the title compound 12 mg (yield 29%) as a pale yellow solid.

MS (ESI) m / e: 486 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 7.06-8.42 (m, 11H), 4.74 (d, 1Ha, J = 16.0Hz), 4.47-4.58 (m, 3H), 4.38 (d, 1Hb, J = 16.0 Hz), 3.56-3.59 (m, 1H), 3.46-3.50 (m, 1H), 2.82-2.85 (m, 2H)

[Example 124]

Synthesis of 4 - (((1- (3- (E) -phenylprop-2-enoyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.33 g (0.87 mmol, Yield: 87%) of the title compound.

MS (ESI) m / e: 378 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.42-1.93 (m, 6H), 2.82 (bs, 0.7H), 3.27 (bs, 0.3H), 3.66 (bs, 1H), 3.80 (bs, 0.3H) , 3.98 (bs, 0.7H), 4.13 (bs, 0.5H), 4.50-4.69 (m, 3H), 5.06 (bs, 0.5H), 7.22 (d, 1H, J = 15.7 Hz), 7.36-7.78 m, 10H)

[Example 125]

Synthesis of 4 - (((1 - ((3- (phenylcarbonyl) phenyl) carbonyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to yield 0.324 g (0.71 mmol, Yield: 71%) of the title compound.

MS (ESI) m / e: 456 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 1.49-1.89 (m, 6H), 2.97 (bs, 1H), 3.40-3.81 (m, 1.5H), 3.95 (bs, 2H), 7.48-7.73 (m, 7H), 7.74-7.90 (m, 4H)

[Example 126]

Synthesis of 4 - (((1- (2- (3-methylphenyl) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.291 g (0.77 mmol, Yield: 77%) of the title compound.

MS (ESI) m / e: 380 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.23-1.49 (m, 2H), 1.49-1.89 (m, 4H), 2.30 (d, 3H, J = 10.4Hz), 2.69 (t, 0.5H, J = 4.55 (d, 0.5H, J = 12.0 Hz), 4.57- (3H, m) 2H, J = 8.1 Hz), 7.81 (m, 2H), 5.02 (bs, 0.5H), 6.99-7.12 (m, 3H), 7.13-7.26 , J = 8.4 Hz), 8.78 (bs, IH), 9.30 (bs, IH)

[Example 127]

Synthesis of 4 - (((1- (2 - ((4-methoxyphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.127 g (0.27 mmol, Yield: 59%) of the title compound.

MS (ESI) m / e: 474 (M) ^&lt; ⁺ & gt ^;

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.27-1.54 (m, 2H), 1.58-1.92 (m, 3H), 2.60 (t, 0.5H, J = 10.0Hz), 2.88-3.09 (m, 1.5H 2H), 3.34-3.46 (m, 3H), 3.81-3.99 (m, 3.5H), 4.24 (d, 0.5H, J = 11.0 Hz), 4.57 2H), 7.41-7.50 (m, 2H), 7.70-7.84 (m, 4H)

[Example 128]

Synthesis of 4 - (((1- (2 - ((2-naphthyl) carbonylamino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.045 g (0.098 mmol, Yield: 34%) of the title compound.

MS (ESI) m / e: 459 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.36-1.65 (m, 2H), 1.65-2.09 (m, 3H), 2.76 (t, 0.5H, J = 10.0Hz), 3.03-3.26 (m, 1.5H 2H), 4.41 (d, 0.5H, J = 12.0 Hz), 4.61 (dt, 1H) 2H, J = 13.0 Hz), 7.48-7.52 (m, 2H), 7.59-7.63 (m, 2H), 7.72-7.77 (m, 2H), 7.93-8.00 (m, 4H), 8.47

[Example 129]

Synthesis of 4 - (((1- (2 - ((4-methoxyphenyl) methyl) amino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.018 g (0.042 mmol, yield 52%) of the title compound.

MS (ESI) m / e: 425 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.22-1.78 (m, 6H), 2.57 (t, 0.5H, J = 12.0Hz), 2.98 (bt, 0.5H), 3.27-3.59 (m, 6.5H) , 3.65 (s, 3H), 3.75 (t, 0.5H, J = 9.6Hz), 4.04 (bs, 0.5H), 4.30 (bd, 0.5H), 4.38-4.58 2H, J = 8.0 Hz), 7.11 (d, 2H, J = 7.6 Hz), 7.23-7.40

[Example 130]

Synthesis of 4 - (((1- (2- (benzylamino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.018 g (0.046 mmol, Yield: 54%) of the title compound.

MS (ESI) m / e: 395 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 1.21-1.78 (m, 6H), 2.58 (bt, 0.5H), 2.97 (bs, 0.5H), 3.26-3.67 H), 4.05 (bs, 0.5H), 4.31 (bd, 0.5H), 4.38-4.59 (m, 2H), 4.82 (bs, 0.5H), 7.07-7.43 , J = 8.3 Hz)

[Example 131]

Synthesis of 4 - (((1- (2 - ((cyclohexylmethyl) amino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.024 g (0.060 mmol, Yield: 61%) of the title compound.

MS (ESI) m / e: 401 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 0.81 (bs, 2H), 1.00-1.24 (m, 3H), 1.25-1.41 (m, 2H), 1.45-1.78 , 2H), 2.59 (bt, 0.5H), 3.01 (bt, 0.5H), 3.26-3.67 (m, 4.5H), 3.79 (tb, 0.5H) 2H), 7.63 (d, 2H, J = 8.3 Hz), 7.50 (q, 2H, J =

[Example 132]

(((1- (2- (S) - ((4-nitrophenyl) methyl) amino) propanoyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.056 g (0.12 mmol, Yield: 54%) of the title compound.

MS (ESI) m / e: 454 (M + H) &lt; ^{+ &}

¹ H-NMR (DMSO-d ₆ )?: 0.98-1.18 (m, 3H), 1.25 (bs, 1H), 1.39-1.81 H), 3.18-3.88 (m, 6.5H), 4.10 (bs, 0.5H), 4.32-4.62 (m, 2.5H), 4.83 (bs, 0.5H) m, 3H), 7.57-7.79 (m, 3H), 8.02-8.22 (m, 2H)

[Example 133]

Amino] propanoyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine The title compound was synthesized in the same manner as in (1)

The reaction was carried out in the same manner as in Example 90 to give 0.046 g (0.10 mmol, Yield 44%) of the title compound.

MS (ESI) m / e: 454 (M + H) &lt; ^{+ &}

¹ H-NMR (DMSO-d ₆ )?: 1.01-1.19 (m, 3H), 1.25 (bs, 1H), 1.37-1.82 (m, 5H), 2.57-2.74 (m, 0.5H), 3.43-3.86 (m, 6.5H), 4.12 (bs, 0.5H), 4.33-4.60 (m, 2.5H), 4.77-4.91 ), 7.21-7.39 (m, 2H), 7.46-7.65 (m, 2H), 7.67-7.81 (m, 2H), 8.01-8.24

[Example 134]

Synthesis of 4 - (((1- (2- (bis (2-naphthylmethyl) -amino) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.135 g (0.23 mmol, Yield: 77%) of the title compound.

MS (ESI) m / e: 585 (M + H) &lt; ^{+ &}

^{1 H-NMR (DMSO-d} 6) δ: 1.24 (bs, 1H), 1.31-1.78 (m, 5H), 2.79-2.99 (m, 1H), 3.12 (bd, 1H), 3.45 (bs, 2H) , 3.53-3.72 (m, 2H), 3.80-4.12 (m, 5H), 4.28 (bd, 0.5H), 4.44 (bs, (d, IH, J = 7.5 Hz), 7.26 (d, IH, J = 6.2 Hz), 7.42-7.71 (m, 8H), 7.79-7.96

[Example 135]

Synthesis of 4 - (((1- (2 - ((4-methylphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.047 g (0.10 mmol, Yield: 35%) of the title compound.

MS (ESI) m / e: 458 (M) +, 460 (M + 2H) +

^{1 H-NMR (DMSO-d} 6) δ: 1.18-1.31 (m, 2H), 1.52-1.85 (m, 3H), 2.38 (s, 3H), 2.73-3.00 (m, 2H), 3.60 (d, J = 12.7 Hz), 3.68 (d, 2H, J = 6.0 Hz), 3.91 (d, 0.5H, J = 13.0 Hz), 4.18 2H), 6.82 (bs, 3H), 7.31-7.41 (m, 4H), 7.67-7.79 (m, 4H), 8.32

[Example 136]

Synthesis of 4 - (((1- (2 - ((2-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.064 g (0.13 mmol, Yield: 66%) of the title compound.

MS (ESI) m / e: 490 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.17-1.36 (m, 3H), 1.62-1.78 (m, 2H), 2.59 (t, 0.5H, J = 12.0Hz), 2.89-3.03 (m, 1.5H 2H), 4.01 (d, 2H), 3.35-3.36 (m, 3H), 3.70-3.81 Hz), 7.41-7.58 (m, 2H), 7.62-7.81 (m, 5H), 7.92-8.02

[Example 137]

Synthesis of 4 - (((1- (2 - ((2-aminophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.125 g (0.27 mmol, Yield: 94%) of the title compound.

MS (ESI) m / e: 460 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.29-1.51 (m, 3H), 1.71-1.88 (m, 2H), 2.59-2.75 (m, 0.5H), 2.91-3.11 (m, 1.5H), 3.39 (M, 2H), 3.51-3.67 (m, 1H), 3.71-3.81 (m, 2H), 3.89-3.99 2H, J = 7.2 Hz), 6.61-6.77 (m, 1H), 6.84 (d, 1H, J = 8.1 Hz), 7.29 (bs, 1H), 7.51-7.67 , J = 7.4 Hz)

[Example 138]

Synthesis of 3 - (((1- (2 - ((2-naphthyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.141 g (0.285 mmol, yield 52%) of the title compound.

MS (ESI) m / e: 495 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.02-1.47 (m, 3H), 1.49-1.71 (m, 2H), 2.41 (t, 0.5H, J = 11.0Hz), 2.73 (t, 0.5H, J (M, 2H), 4.31 (s, 2H), 4.01 (d, 1H), 4.40 (s, 1H), 7.31-7.41 (m, 2H), 7.46-7.64 (m, 4H), 7.71-7.96 (m, 4H), 8.31

[Example 139]

Synthesis of 3 - (((1- (2- (naphthylsulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.32 mmol of the title compound (0.159 g, yield 55%).

MS (ESI) m / e: 495 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.10-1.35 (m, 2H), 1.39-1.71 (m, 3H), 2.41 (t, 0.5H, J = 11.0Hz), 2.66-2.87 (m, 1.5H ), 3.13-3.29 (m, 2H), 3.41-3.58 (m, IH), 3.59-3.76 (m, 2.5H), 3.98 (d, 0.5H, J = 1H), 7.96-8.12 (m, 2H), 8.61-8.70 (m, 1H), 7.29-7.63

[Example 140]

Synthesis of 3 - (((1- (2 - ((4-methoxyphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.157 g (0.331 mmol, Yield: 52%) of the title compound.

MS (ESI) m / e: 495 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.17-1.44 (m, 2H), 1.49-1.82 (m, 3H), 2.52 (t, 0.5H, J = 11.0Hz), 2.89-2.99 (m, 1.5H 3H), 3.81 (bd, 0.5H), 4.12 (d, 0.5H, J = 12.0 Hz), 4.44 (m, 2H), 3.25-3.37 2H, J = 9.4 Hz), 6.88-6.99 (m, 2H), 7.31-7.46 (m, 2H), 7.51-7.72

[Example 141]

Synthesis of 4 - (((1- (2 - ((3-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.070 g (0.14 mmol, Yield: 68%) of the title compound.

MS (ESI) m / e: 490 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.18-1.31 (m, 2H), 1.56-1.83 (m, 3H), 2.49 (t, 0.5H, J = 13.0Hz), 2.73-3.01 (m, 1.5H 1H), 4.56 (s, 1H), 7.46 (q, 2H), 3.29-3.38 (m, 2H), 3.57-3.86 1H, J = 7.3 Hz), 7.61-7.73 (m, 3H), 8.12 (t, 1H, J = 8.2 Hz), 8.31 )

[Example 142]

Synthesis of 4 - (((1- (2 - ((naphthylsulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.048 g (0.097 mmol, Yield: 17%) of the title compound.

MS (ESI) m / e: 495 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 1.12-1.32 (m, 2H), 1.41-1.75 (m, 3H), 2.44 (t, 0.5H, J = 13.0 Hz), 2.74-2.92 ), 3.50 (t, 1H, J = 16.0 Hz), 3.61-3.76 (m, 2.5H), 3.98-4.09 (m, 0.5H), 4.45 (s, 2H), 7.38-7.70 7.91 (d, 1H, J = 7.7 Hz), 7.99-8.17 (m, 2H), 8.62 (d, 1H, J = 8.0 Hz).

[Example 143]

Synthesis of 4 - (((1- (2 - ((2-naphthylsulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.051 g (0.10 mmol, Yield: 18%) of the title compound.

MS (ESI) m / e: 495 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.11-1.29 (m, 2H), 1.38-1.69 (m, 3H), 2.46 (t, 0.5H, J = 13.0Hz), 2.70-3.02 (m, 1.5H ), 3.40-3.60 (m, 1H), 3.67-3.81 (m, 2.5H), 3.98-4.08 (m, 0.5H), 4.39 , 4H), 7.62-7.79 (m, 3H), 7.82-7.99 (m, 3H), 8.33 (d,

[Example 144]

Synthesis of 4 - (((1- (2 - ((3-aminophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.042 g (0.091 mmol, Yield: 47%) of the title compound.

MS (ESI) m / e: 495 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.12-1.38 (m, 2H), 1.51-1.79 (m, 3H), 2.58 (t, 0.5H, J = 13.0Hz), 2.82-3.02 (m, 1.5H 2H, J = 5.9 Hz), 6.77 (d, 2H), 3.29-3.42 (m, 3H), 3.58-3.70 1H, J = 8.0 Hz), 6.91-7.17 (m, 3H), 7.41-7.50 (m, 2H), 7.62-7.71

[Example 145]

(((1- (2 - ((3 - ((methylsulfonyl) amino) phenyl) sulfonyl) amino) ethanoyl) -3-piperidyl) methyloxy) methyl) benzenecarboxamidine Synthesis of

The reaction was carried out in the same manner as in Example 90 to obtain 0.116 g (0.22 mmol, Yield: 57%) of the title compound.

MS (ESI) m / e: 538 (M + H) &lt; ^{+ &}

¹ H-NMR (CD ₃ OD)?: 1.22-1.41 (m, 2H), 1.51-1.84 (m, 3H), 2.51-2.62 , 2.89-3.01 (m, 1.5H), 3.29-3.39 (m, 2H), 3.66-3.82 (m, 2.5H), 4.01-4.12 7.31 (m, 3H), 7.46-7.57 (m, 3H), 7.67-7.76 (m, 2H)

[Example 146]

Synthesis of 3 - (((1- (2 - ((4-methylphenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.16 g (0.35 mmol, Yield: 57%) of the title compound.

MS (ESI) m / e: 459 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.19-1.37 (m, 2H), 1.48-1.81 (m, 3H), 2.30 (s, 3H), 2.51 (t, 0.5H, J = 12.0Hz), 2.79 2H), 3.81 (bd, 0.5H), 4.11 (bd, 0.5H), 3.50-3.66 (m, 2H), 7.53-7.67 (m, 4H), 7.30 (d, 2H, J =

[Example 147]

Synthesis of 3 - (((1- (2 - ((4-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.082 g (0.17 mmol, Yield: 80%) of the title compound.

MS (ESI) m / e: 490 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.18-1.34 (m, 2H), 1.47-1.87 (m, 3H), 2.57 (t, 0.5H, J = 12.0Hz), 2.73-3.07 (m, 1.5H 2H), 7.38-7.71 (m, 4H), 7.88 (m, 2H), 3.28-3.40 -7.98 (m, 2H), 8.21 (t, 2H, J = 9.3 Hz)

[Example 148]

Synthesis of 3 - (((1- (2 - ((2-nitrophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to obtain 0.078 g (0.16 mmol, Yield: 76%) of the title compound.

MS (ESI) m / e: 490 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.18-1.35 (m, 2H), 1.41-1.89 (m, 3H), 2.67 (t, 0.5H, J = 12.0Hz), 2.78-3.08 (m, 1.5H ), 3.27-3.41 (m, 2H), 3.51-3.67 (m, 1H), 3.72-3.90 (m, 2.5H), 3.98-4.09 -7.51 (m, 2H), 7.53-7.73 (m, 5H), 7.89-7.99 (m, 1H)

[Example 149]

Synthesis of 3 - (((1- (2 - ((4-aminophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.059 g (0.13 mmol, Yield: 57%) of the title compound.

MS (ESI) m / e: 460 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.17-1.36 (m, 2H), 1.49-1.82 (m, 3H), 2.59 (t, 0.5H, J = 12.0Hz), 2.82-3.01 (m, 1.5H ), 3.26-3.37 (m, 2H), 3.49-3.69 (m, 3H), 3.81 (d, 0.5H, J = 14.0Hz), 4.12 (d, 0.5H, J = 14.0Hz), 4.42-4.51 (m, 2H), 6.56 (t, 2H, J = 8.7 Hz), 7.36-7. 51 (m, 4H), 7.57 (bs,

[Example 150]

Synthesis of 3 - (((1- (2 - ((2-aminophenyl) sulfonyl) amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine

The reaction was carried out in the same manner as in Example 90 to give 0.051 g (0.11 mmol, Yield: 80%) of the title compound.

MS (ESI) m / e: 460 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ: 1.18-1.31 (m, 2H), 1.49-1.82 (m, 3H), 2.58 (t, 0.5H, J = 12.0Hz), 2.78-2.99 (m, 1.5H (M, 3H), 3.81 (d, 0.5H, J = 13.0Hz), 4.11 (d, 0.5H, J = 14.0Hz), 4.39-4.49 (m, 2H), 6.49-6.61 (m, IH), 6.71 (d, IH, J = 8.7Hz), 7.12-7.21 , 7.63 (bs, 1 H)

[Example 151]

3 - (((1- (2 - ((4 - ((methylsulfonyl) amino) phenyl) sulfonyl) amino) ethanoyl) -3-piperidyl) methyloxy) methyl) benzenecarboxamidine Synthesis of

The reaction was carried out in the same manner as in Example 90 to yield 0.308 g (0.57 mmol, Yield 92%) of the title compound.

MS (ESI) m / e: 538 (M + H) &lt; ^{+ &}

_{^{1 H-NMR (CD 3 OD}} ) δ (HCl salt): 1.19-1.37 (m, 2H), 1.48-1.81 (m, 3H), 2.61 (t, 0.5H, J = 12.0Hz), 2.88-3.02 ( 2H), 7.24 (m, 2H), 3.50-3.79 (m, 3.5H), 4.08 (d, 0.5H, J = 14.0Hz), 4.41-4.52 J = 8.7 Hz), 7.51 (q, 1H, J = 8.2 Hz), 7.60-7.72 (m, 5H)

Experimental Example 1: Measurement of thrombin inhibitory activity

To determine the selective thrombin inhibitory activity of the compounds according to the present invention, IC _{50 values} for thrombin and trypsin were measured at room temperature using microtiter plates, respectively, in the following manner.

Each test compound was dissolved in 50% methanol at various concentrations, and 20 μl of each concentration of the methanol solution was dissolved in 0.05 M Tris hydrochloride buffer, 0.125 M NaCl (pH 8.0, 0.25 M chromogenic substrate N-benzoyl-Phe- Arg-p-nitroanilide), and 20 μl of human thrombin and small trypsin were added to the resulting solution to a final concentration of 0.5 NIH units / ml and 1 unit / ml, respectively, to initiate the enzyme reaction. After the reaction solution was incubated for 20 minutes, the absorbance at 405 nm was measured with a microtiter plate reader, and the degradation of the substrate by the enzyme was calculated by increasing the absorbance. The IC ₅₀ was determined as the inhibitor concentration which inhibited 50% of the enzyme activity when the enzyme activity was 100% in the absence of the inhibitor. The measured results are shown in Table 1 below.

[Table 1]

The thrombin and trypsin inhibitory activity of the compounds of the present invention

As can be seen from the results of Table 1, the compound of Formula 1 according to the present invention showed excellent thrombin inhibitory activity and selectively inhibited thrombin more strongly than trypsin.

Claims (12)

Claims 1. Compounds of the formula 1, pharmaceutically acceptable salts thereof and isomers thereof: [Chemical Formula 1] In this formula, A is or , Wherein m represents an integer of 0 to 2, R ₁ and R ₂ each independently represent hydrogen or together with the carbon atom to which they are attached form a fused benzene ring, n represents an integer of 0 to 2, X represents CH ₂ , CO or SO ₂ , Y represents any one of the following formulas (2) to (8) (2) (3) [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] (7) [Chemical Formula 8] T is Or alkenyl, wherein q represents an integer of 0 to 2, R ₃ represents hydrogen, alkyl, alkoxy, nitro, benzoyl or -NR ₄ R 5 wherein R ₄ and R ₅ each independently represent hydrogen or alkylsulfonyl, R &lt; ₆ &gt; represents hydrogen or alkyl, D is Cycloalkyl or naphthyl, R &lt; 7 &gt; represents hydrogen or alkylsulfonyl, R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ each independently represent hydrogen, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl or carbamoylalkyl, E represents cycloalkyl, R ₁₁ and R ₁₂ each independently represent naphthylalkyl. The method according to claim 1, A is , Wherein m represents 0 or 1, R1 and R2 each independently represent hydrogen or form a fused benzene ring together with the carbon atom to which they are attached, n represents 0 or 1, X represents CH ₂ , CO or SO ₂ , Y represents any one of the groups represented by formulas (2) to (8) defined in claim 1, T is Or ethenyl, wherein q is an integer from 0 to 2, R ₃ represents hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, benzoyl or -NR ₄ R ₅ wherein R ₄ and R ₅ are each independently hydrogen or C ₁ -C ₄ alkyl Sulfinyl, R ₆ represents hydrogen or C ₁ -C ₄ alkyl, D is , C ₄ -C ₇ cycloalkyl or naphthyl, R ₇ represents hydrogen or C ₁ -C ₄ alkylsulfonyl, R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, hydroxycarbonyl lower alkyl, lower alkoxycarbonyl lower alkyl, C ₁ -C ₄ alkylsulfonyl or carbamoyl lower Alkyl, E represents C ₄ -C ₇ cycloalkyl, R ₁₁ and R ₁₂ each independently represent naphthylmethyl. 3. The method of claim 2, A is , Wherein m represents 0 or 1, R ₁ and R ₂ each independently represent hydrogen or together with the carbon atom to which they are attached form a fused benzene ring, n represents 0 or 1, X represents CH ₂ , CO or SO ₂ , Y represents any one of the groups represented by formulas (2) to (8) defined in claim 1, T is Or ethenyl, wherein q is T Lt; 2 &gt; is an integer of 0 to 2 and T is 1 &quot;, &quot; R ₃ represents hydrogen, methyl, methoxy, nitro, benzoyl or -NR ₄ R ₅ wherein R ₄ and R ₅ each independently represent hydrogen or methylsulfonyl, R &lt; ₆ &gt; represents hydrogen or methyl, D is Cyclohexyl or naphthyl, R &lt; ₇ &gt; represents hydrogen or methylsulfonyl, R ₈ represents -NR ₉ R ₁₀ wherein R ₉ and R ₁₀ are each independently hydrogen, hydroxycarbonylmethyl, ethoxycarbonylmethyl, methylsulfonyl or carbamoylmethyl, E represents cyclohexyl, R ₁₁ and R ₁₂ each independently represent naphthylmethyl. The method of claim 3, 4 - (((1 - ((4-methoxyphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine, 4 - (((1 - ((4-methylphenyl) sulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine, 4 - (((1- (naphthylsulfonyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine, Propyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine, 2-methyl-2- 4 - (((1- (S) - (3-phenylpropanoyl) pyrrolidin-2-yl) methoxy) methyl) benzenecarboxamidine, 4 - (((1- (2- (3-methylphenyl) acetyl) -2-piperidyl) methoxy) methyl) benzenecarboxamidine, and Amino) acetyl) -3-piperidyl) methoxy) methyl) benzenecarboxamidine of formula (I). A thrombin inhibitor composition comprising a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient in combination with a pharmaceutically acceptable carrier. The thrombin inhibitor composition according to claim 5, for use as a thrombosis prevention and treatment agent. (a) reacting a compound of the following formula (9) with a compound of the following formula (10) to obtain a compound of the formula (17a) (b) reacting a compound of the formula (11) or a salt thereof with a compound of the following formula (12) to obtain a compound of the formula (17) (c) reacting a compound of the following formula (13) with a compound of the following formula (14) to obtain a compound of the formula (17b) (d) reacting a compound of the following formula (15) or a salt thereof with a compound of the following formula (16) to obtain a compound of the formula (17c) wherein Y is a group of the formula (3) (e) preparing a compound of the formula (1) as defined in claim 1, characterized in that the cyano group of the compound prepared by any one of the above methods (a) to (d) is converted into an amidino group Way: [Chemical Formula 9] [Chemical formula 10] [Formula 17a] (11) [Chemical Formula 12] L-X-Y [Chemical Formula 17] [Chemical Formula 13] [Chemical Formula 14] [Formula 17b] [Chemical Formula 15] [Chemical Formula 16] L-X-D [Chemical Formula 17c] In the above formula Wherein A, R ₁ , R ₂ , R ₆ , n, m, X, Y and D are as defined in claim 1, L represents a leaving group. A compound of formula (17): [Chemical Formula 17] Compounds of formula 10: [Chemical formula 10] A compound of the formula (11): &lt; EMI ID = (11) A compound of the formula 14: [Chemical Formula 14] A compound of the formula (15): &lt; EMI ID = [Chemical Formula 15]